Alpha-conotoxin peptides

ABSTRACT

The invention relates to relatively short peptides (termed α-conotoxins herein), about 10-30 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogous to the naturally available peptides, and which preferably include two disulfide bonds.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a division of U.S. patent application Ser.No. 12/706,911 filed 17 Feb. 2010, now U.S. Pat. No. 7,902,153, which inturn is a division of U.S. patent application Ser. No. 11/869,480 filed9 Oct. 2007, now U.S. Pat. No. 7,666,840, which in turn is a division ofU.S. patent application Ser. No. 10/895,372 filed 21 Jul. 2004, now U.S.Pat. No. 7,279,549, which in turn is a division of U.S. patentapplication Ser. No. 09/493,795 filed 28 Jan. 2000, now U.S. Pat. No.6,797,808. U.S. patent application Ser. No. 09/493,795 is related to andclaims priority under 35 U.S.C. §119(e) to U.S. provisional patentapplication Ser. No. 60/118,381, filed 29 Jan. 1999. Each application isincorporated herein by reference.

This invention was made with Government support under Grant No. PO1GM48677 awarded by the National Institute of General Medical Sciences,National Institutes of Health, Bethesda, Md. The United StatesGovernment has certain rights in the invention.

SEQUENCE SUBMISSION

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is entitled2323248SequenceListing.txt, was created on 7 Mar. 2011 and is 252 kb insize. The information in the electronic format of the Sequence Listingis part of the present application and is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

The invention relates to relatively short peptides (termed α-conotoxinsherein), about 10-30 residues in length, which are naturally availablein minute amounts in the venom of the cone snails or analogous to thenaturally available peptides, and which preferably include two disulfidebonds.

The publications and other materials used herein to illuminate thebackground of the invention, and in particular, cases to provideadditional details respecting the practice, are incorporated byreference, and for convenience are referenced in the following text byauthor and date and are listed alphabetically by author in the appendedbibliography.

The predatory cone snails (Conus) have developed a unique biologicalstrategy. Their venom contains relatively small peptides that aretargeted to various neuromuscular receptors and may be equivalent intheir pharmacological diversity to the alkaloids of plants or secondarymetabolites of microorganisms. Many of these peptides are among thesmallest nucleic acid-encoded translation products having definedconformations, and as such, they are somewhat unusual. Peptides in thissize range normally equilibrate among many conformations. Proteinshaving a fixed conformation are generally much larger.

The cone snails that produce these peptides are a large genus ofvenomous gastropods comprising approximately 500 species. All cone snailspecies are predators that inject venom to capture prey, and thespectrum of animals that the genus as a whole can envenomate is broad. Awide variety of hunting strategies are used; however, every Conusspecies uses fundamentally the same basic pattern of envenomation.

Several peptides isolated from Conus venoms have been characterized.These include the α-, μ- and ω-conotoxins which target nicotinicacetylcholine receptors, muscle sodium channels, and neuronal calciumchannels, respectively (Olivera et al., 1985). Conopressins, which arevasopressin analogs, have also been identified (Cruz et al. 1987). Inaddition, peptides named conantokins have been isolated from Conusgeographus and Conus tulipa (Mena et al., 1990; Haack et al., 1990).

The α-conotoxins are small peptides highly specific for neuromuscularjunction nicotinic acetylcholine receptors (Gray et al., 1981; Marshalland Harvey, 1990; Blount et al., 1992; Jacobsen et al., 1997) or highlyspecific for neuronal nicotinic acetylcholine receptors (Fainzilber etal., 1994; Johnson et al., 1995; Cartier et al., 1996; Luo et al.,1998). The a-conotoxins with specificity for neuromuscular junctionnicotinic acetylcholine receptors are used as neuromuscular blockingagents for use in conjunction with surgery, as disclosed in U.S. patentapplication Ser. No. 09/488,799, filed 21 Jan. 2000, incorporated byreference herein. Additional α-conotoxins and uses for them have beendescribed in U.S. Pat. Nos. 4,447,356 (Olivera et al., 1984); 5,432,155;5,514,774, each incorporated herein by reference.

Additional uses for α-conotoxins are described in U.S. Ser. No.09/219,446, filed 22 Dec. 1998, incorporated herein by reference. Inthis application, α-conotoxins with specificity for neuronal nicotinicacetylcholine receptors are used for treating disorders regulated atneuronal nicotinic acetylcholine receptors. Such disorders include, butare not limited to, cardiovascular disorders, gastric motilitydisorders, urinary incontinence, nicotine addiction, mood disorders(such as bipolar disorder, unipolar depression, dysthymia and seasonaleffective disorder) and small cell lung carcinoma, as well as thelocalization of small cell lung carcinoma.

It is desired to provide additional α-conotoxin peptides having uses asdescribed herein.

SUMMARY OF THE INVENTION

The invention relates to relatively short peptides (termed α-conotoxinsherein), about 10-30 residues in length, which are naturally availablein minute amounts in the venom of the cone snails or analogous to thenaturally available peptides, and which preferably include two disulfidebonds.

More specifically, the present invention is directed to α-conotoxinpeptides having the general formula I:

Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Cys-Cys-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Cys-Xaa₁₀-Xaa₁₁-Xaa₁₂-Cys-Xaa₁₃(SEQ ID NO 1:), wherein Xaa₁ is des-Xaa₁, Ile, Leu or Val; Xaa₂ isdes-Xaa₂, Ala or Gly; Xaa₃ is des-Xaa₃, Gly, Trp (D or L), neo-Trp,halo-Trp or any unnatural aromatic amino acid; Xaa₄ is des-Xaa₄, Asp,Phe, Gly, Ala, Glu, γ-carboxy-Glu (Gla) or any unnatural aromatic aminoacid; Xaa₅ is Glu, Gla, Asp, Ala, Thr, Ser, Gly, Ile, Tyr, nor-Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr orany unnatural hydroxy containing amino acid; Xaa₆ is Ser, Thr, Arg,ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys,N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa₇ is Asp, Glu,Gla, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys,N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa₈ is Ser, Thr,Asn, Ala, Gly, Arg, Lys, ornithine, homoarginine, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid,His, halo-His, Pro or hydroxy-Pro; Xaa₉ is Thr, Ser, Ala, Asp, Asn, Pro,hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid;Xaa₁₀ is Gly, Ser, Thr, Ala, Asn, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₁₁ is Gln, Leu, His, halo-His, Trp (D or L),halo-Trp, neo-Trp, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Arg, ornithine, homoarginine,Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnaturalbasic amino acid or any unnatural aromatic amino acid; Xaa₁₂ is Asn,His, halo-His, Ile, Leu, Val, Gln, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₁₃ is des-Xaa₁₃, Val, Ile, Leu, Arg, ornithine,homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lysor any unnatural basic amino acid. The C-terminus may contain a freecarboxyl group or an amide group. The halo is chlorine, bromine oriodine, preferably iodine for Tyr and His and preferably bromine forTrp. The Cys residues may be in D or L configuration and may optionallybe substituted with homocysteine (D or L). The Tyr residues may besubstituted with the 3-hydroxyl or 2-hydroxyl isomers and correspondingO-sulpho- and O-phospho-derivatives. The acidic amino acid residues maybe substituted with any synthetic acidic bioisoteric amino acidsurrogate, e.g., tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to α-conotoxinpeptides having the general formula II:

Xaa₁-Xaa₂-Xaa₃-Xaa₄-Cys-Cys-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Cys-Xaa₉-Xaa₁₀-Xaa₁₁-Xaa₁₂-Xaa₁₃-Xaa₁₄-Cys-Xaa₁₅-Xaa₁₆-Xaa₁₇(SEQ ID NO: 2), wherein Xaa₁ is des-Xaa₁, Asp, Glu or γ-carboxy-Glu(Gla); Xaa₂ is des-Xaa₂, Gln, Ala, Asp, Glu, Gla; Xaa₃ is des-Xaa₃, Gly,Ala, Asp, Glu, Gla, Pro or hydroxy-Pro; Xaa₄ is des-Xaa₄, Gly, Glu, Gla,Gln, Asp, Asn, Pro or hydroxy-Pro; Xaa₅ is Ser, Thr, Gly, Glu, Gla, Asn,Trp (D or L), neo-Trp, halo-Trp, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basicamino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid;Xaa₆ is Asp, Asn, His, halo-His, Thr, Ser, Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnaturalhydroxy containing amino acid; Xaa₇ is Pro or hydroxy-Pro; Xaa₈ is Ala,Ser, Thr, Asp, Val, Ile, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnaturalhydroxy containing amino acid; Xaa₉ is Gly, Ile, Leu, Val, Ala, Thr,Ser, Pro, hydroxy-Pro, Phe, Trp (D or L), neo-Trp, halo-Trp, Arg,ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys,N,N,N-trimethyl-Lys, any unnatural basic amino acid or any unnaturalaromatic amino acid; Xaa₁₀ is Ala, Asn, Phe, Pro, hydroxy-Pro, Glu, Gla,Gln, His, halo-His, Val, Ser, Thr, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₁₁ is Thr, Ser, His, halo-His, Leu, Ile, Val, Asn,Met, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid,Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa₁₂ is Asn,Pro, hydroxy-Pro, Gln, Ser, Thr, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys N,N,N-trimethyl-Lys, any unnatural basicamino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid;Xaa₁₃ is des-Xaa₁₃, Gly, Thr, Ser, Pro, hydroxy-Pro, Tyr, nor-Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr orany unnatural hydroxy containing amino acid; Xaa₁₄ is des-Xaa₁₄, Ile,Val, Asp, Leu, Phe, Arg, ornithine, homoarginine, Lys, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid,Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr or any unnatural hydroxy containing amino acid; and Xaa₁₅ isdes-Xaa₁₅, Gly, Ala, Met, Ser, Thr, Trp (D or L), neo-Trp, halo-Trp, anyunnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₁₆ is des-Xaa₁₆, Trp (D or L), neo-Trp, halo-Trp,any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₁₇ is des-Xaa₁₇, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid. The C-terminus may contain a free carboxyl group or anamide group. The halo is preferably bromine, chlorine or iodine, morepreferably iodine for His or Tyr and bromine for Trp. The Cys residuesmay be in D or L configuration and may optionally be substituted withhomocysteine (D or L). The Tyr residues may be substituted with the3-hydroxyl or 2-hydroxyl isomers and corresponding O-sulpho- andO-phospho-derivatives. The acidic amino acid residues may be substitutedwith any synthetic acidic bioisoteric amino acid surrogate, e.g.,tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to α-conotoxinpeptides having the general formula III:

Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Cys-Cys-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Cys-Xaa₁₀-Xaa₁₁-Xaa₁₂-Xaa₁₃-Xaa₁₄-Xaa₁₅-Xaa₁₆-Cys-Xaa₁₇-Xaa₁₈-Xaa₁₉-Xaa₂₀-Xaa₂₁-Xaa₂₂-Xaa₂₃-Xaa₂₄(SEQ ID NO: 3), wherein Xaa₁ is des-Xaa₁, Ser or Thr; Xaa₂ is des-Xaa₂,Asp, Glu, γ-carboxy-Glu (Gla), Asn, Ser or Thr; Xaa₃ is des-Xaa₃, Ala,Gly, Asn, Ser, Thr, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₄ is des-Xaa₄, Ala, Val, Leu, Ile, Gly, Glu, Gla,Gln, Asp, Asn, Phe, Pro, hydroxy-Pro or any unnatural aromatic aminoacid; Xaa₅ is des-Xaa₅, Thr, Ser, Asp, Glu, Gla, Gln, Gly, Val, Asp,Asn, Ala, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₆ is Thr, Ser, Asp, Asn, Met, Val, Ala, Gly, Leu,Ile, Phe, any unnatural aromatic amino acid, Pro, hydroxy-Pro, Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa₇ is Ile,Leu, Val, Ser, Thr, Gln, Asn, Asp, Arg, His, halo-His, Phe, anyunnatural aromatic amino acid, homoarginine, ornithine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basicamino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid;Xaa₈ is Pro, hydroxy-Pro, Ser, Thr, Ile, Asp, Leu, Val, Gly, Ala, Phe,any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₉ is Val, Ala, Gly, Ile, Leu, Asp, Ser, Thr, Pro,hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid;Xaa₁₀ is His, halo-His, Arg, homoarginine, ornithine, Lys, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid,Asn, Ala, Ser, Thr, Phe, Ile, Leu, Gly, Trp (D or L), neo-Trp, halo-Trp,any unnatural aromatic amino acid, Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnaturalhydroxy containing amino acid; Xaa₁₁ is Leu, Gln, Val, Ile, Gly, Met,Ala, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Ser, Thr,Arg, homoarginine, ornithine, any unnatural basic amino acid, Asn, Glu,Gla, Gln, Phe, Trp (D or L), neo-Trp, halo-Trp or any unnatural aromaticamino acid; Xaa₁₂ is Glu, Gla, Gln, Asn, Asp, Pro, hydroxy-Pro, Ser,Gly, Thr, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Arg,homoarginine, ornithine, any unnatural basic amino acid, Phe, His,halo-His, any unnatural aromatic amino acid, Leu, Met, Gly, Ala, Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa₁₃ is His,halo-His, Asn, Thr, Ser, Ile, Val, Leu, Phe, any unnatural aromaticamino acid, Arg, homoarginine, ornithine, Lys, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid,Tyr, nor-Try, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa₁₄ is Ser,Thr, Ala, Gln, Pro, hydroxy-Pro, Gly, Ile, Leu, Arg, ornithine,homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lysor any unnatural basic amino acid; Xaa₁₅ is Asn, Glu, Gla, Asp, Gly,His, halo-His, Ala, Leu, Gln, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basicamino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid;Xaa₁₆ is Met, Ile, Thr, Ser, Val, Leu, Pro, hydroxy-Pro, Phe, anyunnatural aromatic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, any unnatural hydroxy containingamino acid, Glu, Gla, Ala, His, halo-His, Arg, ornithine, homoarginine,Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or anyunnatural basic amino acid; Xaa₁₇ is des-Xaa₁₇, Gly, Asp, Asn, Ala, Ile,Leu, Ser, Thr, His, halo-His, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₁₈ is des-Xaa₁₈, Gly, Glu, Gla, Gln, Trp (D or L),neo, halo-Trp, any unnatural aromatic amino acid, Arg, ornithine,homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lysor any unnatural basic amino acid; Xaa₁₉ is des-Xaa₁₉, Ser, Thr, Val,Ile, Ala, Arg, ornithine, homoarginine, Lys, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid;Xaa₂₀ is des-Xaa₂₀, Val, Asp, His, halo-His, Arg, ornithine,homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lysor any unnatural basic amino acid; Xaa₂₁ is des-Xaa₂₁, Asn, Pro orhydroxy-Pro; Xaa₂₂ is des-Xaa₂₂, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₂₃ is des-Xaa₂₃, Ser or Thr; Xaa₂₄ is des-Xaa₂₄,Leu, Ile or Val; with the proviso that (a) Xaa₅ is not Gly, when Xaa₁ isdes-Xaa₁, Xaa₂ is des-Xaa₂, Xaa₃ is des-Xaa₃, Xaa₄ is des-Xaa₄, Xaa₆ isSer, Xaa₇ is His, Xaa₈ is Pro, Xaa₉ is Ala, Xaa₁₀ is Ser, Xaa₁₁ is Val,Xaa₁₂ is Asn, Xaa₁₃ is Asn, Xaa₁₄ is Pro, Xaa₁₅ is Asp, Xaa₁₆ is Ile,Xaa₁₇ is des-Xaa₁₇, Xaa₁₈ is des-Xaa₁₈, Xaa₁₉ is des-Xaa₁₉, Xaa₂₀ isdes-Xaa₂₀, Xaa₂₁ is des-Xaa₂₁, Xaa₂₂ is des-Xaa₂₂, Xaa₂₃ is des-Xaa₂₃,and Xaa₂₄ is des-Xaa₂₄. The C-terminus may contain a free carboxyl groupor an amide group. The halo is preferably bromine, chlorine or iodine,more preferably iodine for His and Tyr and bromine for Trp. The Cysresidues may be in D or L configuration and may optionally besubstituted with homocysteine (D or L). The Tyr residues may besubstituted with the 3-hydroxyl or 2-hydroxyl isomers and correspondingO-sulpho- and O-phospho-derivatives. The acidic amino acid residues maybe substituted with any synthetic acidic bioisoteric amino acidsurrogate, e.g., tetrazolyl derivatives of Gly and Ala.

The present invention is also directed to novel specific α-conotoxinpeptides of general formula I having the formulas:

(SEQ ID NO: 4) Asp-Xaa₁-Cys-Cys-Ser-Asp-Ser-Arg-Cys-Gly-Xaa₂-Asn-Cys-Leu; (SEQ ID NO: 5)Ala-Cys-Cys-Ser-Asp-Arg-Arg-Cys-Arg-Xaa₃-Arg- Cys; (SEQ ID NO: 6)Phe-Thr-Cys-Cys-Arg-Arg-Gly-Thr-Cys-Ser-Gln- His-Cys; (SEQ ID NO: 7)Asp-Xaa₄-Cys-Cys-Arg-Arg-His-Ala-Cys-Thr-Leu- Ile-Cys; (SEQ ID NO: 8)Asp-Xaa₄-Cys-Cys-Arg-Xaa₅-Xaa₅-Cys-Thr-Leu-Ile- Cys; (SEQ ID NO: 9)Gly-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Arg-Xaa₄-Arg- Cys-Arg; (SEQ ID NO: 10)Gly-Gly-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ala-Xaa₃- Arg-Cys; (SEQ ID NO: 11)Ile-Ala-Xaa₃-Asp-Ile-Cys-Cys-Ser-Xaa₁-Xaa₅-Asp-Cys-Asn-His-Xaa₂-Cys-Val; and (SEQ ID NO: 12)Gly-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Xaa₂-His-Gln- Cys,wherein Xaa₁ is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys,N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Trp (D or L), halo-Trpor neo-Trp; Xaa₄ is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ is Pro orhydroxy-Pro; and the C-terminus contains a carboxyl or amide group. Thehalo is preferably bromine, chlorine or iodine, more preferably iodinefor Tyr and bromine for Trp. In addition, the His residues may besubstituted with halo-His; the Arg residues may be substituted by Lys,ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys,N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Lys residuesmay be substituted by Arg, ornithine, homoarginine, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid;the Tyr residues may be substituted with any unnatural hydroxycontaining amino acid; the Ser residues may be substituted with Thr; theThr residues may be substituted with Ser; and the Phe and Trp residuesmay be substituted with any unnatural aromatic amino acid. The Cysresidues may be in D or L configuration and may optionally besubstituted with homocysteine (D or L). The Tyr residues may besubstituted with the 3-hydroxyl or 2-hydroxyl isomers and correspondingO-sulpho- and O-phospho-derivatives. The acidic amino acid residues maybe substituted with any synthetic acidic bioisoteric amino acidsurrogate, e.g., tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to the followingα-conotoxin peptides of general formula I:

Im1.1: SEQ ID NO: 4, wherein Xaa₁ is Glu and Xaa₂ is Lys; Im1.2: SEQ IDNO: 5, wherein Xaa₃ is Trp; Rg1.2: SEQ ID NO: 6; Rg1.6: SEQ ID NO: 7,wherein Xaa₄ is Tyr; Rg1.6A: SEQ ID NO: 8, wherein Xaa₄ is Tyr and Xaa₅is Pro; Rg1.7: SEQ ID NO: 9, wherein Xaa₄ is Tyr and Xaa₅ is Pro; Rg1.9:SEQ ID NO: 10, wherein Xaa₃ is Trp and Xaa₅ is Pro; Rg1.10: SEQ ID NO:11, wherein Xaa₁ is Glu, Xaa₂ is Lys, Xaa₃ is Trp and Xaa₅ is Pro; andRg1.11: SEQ ID NO: 12, wherein Xaa₂ is Lys and Xaa₅ is Pro.The C-terminus of Im1.1, Rg1.7 an Rg1.10 preferably contains a freecarboxyl group. The C-terminus of Im1.2, Rg1.2, Rg1.6, Rg1.6A, Rg1.9 andRg1.11 preferably contains an amide group.

The present invention is further directed to novel specific α-conotoxinpeptides of general formula II having the formulas:

(SEQ ID NO: 13) Cys-Cys-Ser-Asp-Xaa₅-Ala-Cys-Xaa₂-Gln-Thr-Xaa₅-Gly-Cys-Arg; (SEQ ID NO: 14)Cys-Cys-Xaa₁-Asn-Xaa₅-Ala-Cys-Arg-His-Thr-Gln- Gly-Cys; (SEQ ID NO: 15)Gly-Cys-Cys-Xaa₃-His-Xaa₅-Ala-Cys-Gly-Arg-His- Xaa₄-Cys; (SEQ ID NO: 16)Ala-Xaa₅-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂- His-Arg-Cys;(SEQ ID NO: 17) Ala-Xaa₅-Gly-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂-His-Arg-Cys; (SEQ ID NO: 18)Xaa₅-Xaa₅-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂- His-Arg-Cys;(SEQ ID NO: 19) Asp-Xaa₁-Asn-Cys-Cys-Xaa₃-Asn-Xaa₅-Ser-Cys-Xaa₅-Arg-Xaa₅-Arg-Cys-Thr; (SEQ ID NO: 20)Gly-Cys-Cys-Ser-Thr-Xaa₅-Xaa₅-Cys-Ala-Val-Leu- Xaa₄-Cys; (SEQ ID NO: 21)Gly-Cys-Cys-Gly-Asn-Xaa₅-Asp-Cys-Thr-Ser-His- Ser-Cys; (SEQ ID NO: 42)Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ala-His-Asn- Asn-Xaa₅-Asp-Cys-Arg;(SEQ ID NO: 154) Gly-Cys-Cys-Xaa₄-Asn-Xaa₅-Val-Cys-Xaa₂-Xaa₂-Xaa₄-Xaa₄-Cys-Xaa₃-Xaa₂; (SEQ ID NO: 155)Xaa₆-Xaa₁-Xaa₅-Gly-Cys-Cys-Arg-His-Xaa₅-Ala- Cys-Gly-Xaa₂-Asn-Arg-Cys;(SEQ ID NO: 156) Cys-Cys-Ala-Asp-Xaa₅-Asp-Cys-Arg-Phe-Arg- Xaa₅-Gly-Cys;(SEQ ID NO: 157) Gly-Cys-Cys-Xaa₄-Asn-Xaa₅-Ser-Cys-Xaa₃-Xaa₅-Xaa₂-Thr-Xaa₄-Cys-Ser-Xaa₃-Xaa₂; (SEQ ID NO: 158)Cys-Cys-Ser-Asn-Xaa₅-Thr-Cys-Xaa₂-Xaa₁-Thr- Xaa₄-Gly-Cys;(SEQ ID NO: 159) Cys-Cys-Ala-Asn-Xaa₅-Ile-Cys-Xaa₂-Asn-Thr-Xaa₅-Gly-Cys; (SEQ ID NO: 160)Cys-Cys-Asn-Asn-Xaa₅-Thr-Cys-Xaa₂-Xaa₁-Thr- Xaa₄-Gly-Cys;(SEQ ID NO: 161) Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Xaa₂-Xaa₁-Thr-Xaa₄-Gly-Cys; (SEQ ID NO: 162)Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Ser-Asn-Xaa₅-Xaa₂-Cys-Gly; (SEQ ID NO: 163)Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Ser-Ala- Met-Ser-Xaa₅-Ile-Cys;(SEQ ID NO: 164) Gly-Cys-Cys-Xaa₂-Asn-Xaa₅-Xaa₄-Cys-Gly-Ala-Ser-Xaa₂-Thr-Xaa₄-Cys; (SEQ ID NO: 165)Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Phe-Ala- Thr-Asn-Xaa₅-Asp-Cys;(SEQ ID NO: 166) Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn-Asn-Xaa₅-Leu-Cys-Ala; (SEQ ID NO: 167)Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn-Asn-Xaa₅-Phe-Cys-Ala; (SEQ ID NO: 168)Asp-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ser-Gln- Asn-Asn-Xaa₅-Asp-Cys-Met; and(SEQ ID NO: 169) Asp-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ala-His-Asn-Asn-Xaa₅-Asp-Cys-Arg,wherein Xaa₁ is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys,N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Trp (D or L), halo-Trpor neo-Trp; Xaa₄ is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ is Pro orhydroxy-Pro; and the C-terminus contains a carboxyl or amide group. Thehalo is preferably bromine, chlorine or iodine, more preferably iodinefor Tyr and bromine for Trp. In addition, the His residues may besubstituted with halo-His; the Arg residues may be substituted by Lys,ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys,N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Lys residuesmay be substituted by Arg, ornithine, homoarginine, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid;the Tyr residues may be substituted with any unnatural hydroxycontaining amino acid; the Ser residues may be substituted with Thr; theThr residues may be substituted with Ser; and the Phe and Trp residuesmay be substituted with any unnatural aromatic amino acid. The Cysresidues may be in D or L configuration and may optionally besubstituted with homocysteine (D or L). The Tyr residues may besubstituted with the 3-hydroxyl or 2-hydroxyl isomers and correspondingO-sulpho- and O-phospho-derivatives. The acidic amino acid residues maybe substituted with any synthetic acidic bioisoteric amino acidsurrogate, e.g., tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to the followingα-conotoxin peptides of general formula II:

Sn1.1: SEQ ID NO: 13, wherein Xaa₂ is Lys and Xaa₅ is Pro; Sn1.2: SEQ IDNO: 14, wherein Xaa₁ is Glu and Xaa₅ is Pro; Sl1.3: SEQ ID NO: 15,wherein Xaa₃ is Trp, Xaa₄ is Tyr and Xaa₅ is Pro; A1.2: SEQ ID NO: 16,wherein Xaa₂ is Lys and Xaa₅ is Pro; Bu1.1: SEQ ID NO: 17, wherein Xaa₂is Lys and Xaa₅ is Pro; Bu1.2: SEQ ID NO: 18, wherein Xaa₂ is Lys andXaa₅ is Pro; Bu1.3: SEQ ID NO: 19, wherein Xaa₁ is Glu, Xaa₃ is Trp andXaa₅ is Pro; Bu1.4: SEQ ID NO: 20, wherein Xaa₄ is Tyr and Xaa₅ is Pro;Cr1.3: SEQ ID NO: 21, wherein Xaa₅ is Pro; Di1.1: SEQ ID NO: 42 whereinXaa₅ is Pro; Ms1.7: SEQ ID NO: 154, wherein Xaa₂ is Lys, Xaa₃ is Trp,Xaa₄ is Tyr and Xaa₅ is Pro; P1.7: SEQ ID NO: 155, wherein Xaa₁ is Glu,Xaa₂ is Lys, Xaa₅ is Pro and Xaa₆ is Gln; Ms1.2: SEQ ID NO: 156, whereinXaa₅ is Pro; Ms1.3: SEQ ID NO: 157, wherein Xaa₂ is Lys, Xaa₃ is Trp,Xaa₄ is Tyr and Xaa₅ is Pro; Ms1.4: SEQ ID NO: 158, wherein Xaa₁ is Glu,Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro; Ms1.5: SEQ ID NO: 159, whereinXaa₂ is Lys and Xaa₅ is Pro; Ms1.8: SEQ ID NO: 160, wherein Xaa₁ is Glu,Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro; Ms1.9: SEQ ID NO: 161, whereinXaa₁ is Glu, Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro; Bt1.7: SEQ ID NO:162, wherein Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro; Lv1.5: SEQ ID NO:163, wherein Xaa₅ is Pro; Ms1.10: SEQ ID NO: 164, wherein Xaa₂ is Lys,Xaa₄ is Tyr and Xaa₅ is Pro; Om1.1: SEQ ID NO: 165, wherein Xaa₄ is Tyrand Xaa₅ is Pro; R1.6: SEQ ID NO: 166, wherein Xaa₄ is Tyr and Xaa₅ isPro; R1.7: SEQ ID NO: 167, wherein Xaa₄ is Tyr and Xaa₅ is Pro; Vr1.1:SEQ ID NO: 168, wherein Xaa₅ is Pro; and Vr1.2: SEQ ID NO: 169, whereinXaa₅ is Pro.The C-terminus preferably contains a carboxyl group for the peptidesSn1.1, Sn1.2, Cr1.3, Di1.1, Ms1.2, Ms1.4, Ms1.5, Ms1.8, Ms1.9, Vr1.1 andVr1.2. The C-terminus of the other peptides preferably contains an amidegroup.

The present invention is also directed to novel specific α-conotoxinpeptides of general formula III having the formulas:

(SEQ ID NO: 22) Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Leu-Xaa₁-His-Ser-Asn-Met-Cys; (SEQ ID NO: 23)Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Arg-Gln-Asn- Asn-Ala-Xaa₁-Xaa₄-Cys-Arg;(SEQ ID NO: 24) Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 25)Xaa₅-Xaa₁-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 26)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Asp; (SEQ ID NO: 27)Xaa₅-Arg-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 28)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Gly-Ile-Cys-Arg; (SEQ ID NO: 29)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Thr-Cys-Arg; (SEQ ID NO: 30)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Val-Cys-Arg; (SEQ ID NO: 31)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Ile-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 32)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg-Arg-Arg-Arg; (SEQ ID NO: 33)Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Val- Asn-His-Xaa₅-Xaa₁-Leu-Cys;(SEQ ID NO: 34) Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Val-Asn-His-Xaa₅-Xaa₁-Leu-Cys; (SEQ ID NO: 35)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp- His-Xaa₅-Xaa₁-Ile-Cys;(SEQ ID NO: 36) Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Xaa₂-Thr-Gln-Xaa₁-Xaa₅-Cys-Arg-Xaa₁-Ser; (SEQ ID NO: 37)Xaa₅-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Xaa₅-Xaa₁-Phe-Cys-Arg-Gln; (SEQ ID NO: 38)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Xaa₅-Xaa₁-Phe-Cys-Arg-Gln; (SEQ ID NO: 39)Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Ala-Met-Asn- Asn-Xaa₅-Asp-Xaa₄-Cys;(SEQ ID NO: 40) Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Phe-Leu-Asn-Asn-Xaa₅-Asp-Xaa₄-Cys; (SEQ ID NO: 41)Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ile-Ala-Xaa₂-Asn-Xaa₅-His-Met-Cys-Gly; (SEQ ID NO: 43)Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn-Xaa₅-His-Val-Cys-Arg-Gln; (SEQ ID NO: 44)Gly-Cys-Cys-Ser-Arg-Xaa₅-Ala-Cys-Ile-Ala-Asn- Asn-Xaa₅-Asp-Leu-Cys;(SEQ ID NO: 45) Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Val-Xaa₁-His-Xaa₅-Xaa₁-Leu-Cys-Arg-Arg-Arg-Arg; (SEQ ID NO: 46)Gly-Gly-Cys-Cys-Ser-Phe-Xaa₅-Ala-Cys-Arg-Xaa₂-Xaa₅-Arg-Xaa₅-Xaa₁-Met-Cys-Gly; (SEQ ID NO: 47)Xaa₅-Xaa₁-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Ser-Ser-His-Xaa₅-Xaa₁-Leu-Cys-Gly; (SEQ ID NO: 48)Xaa₅-Gln-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Val-Gly-His-Xaa₅-Xaa₁-Leu-Cys-Gly; (SEQ ID NO: 49)Xaa₆-Val-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Val-Gly-His-Xaa₅-Xaa₁-Ile-Cys-Gly; (SEQ ID NO: 50)Gly-Cys-Cys-Ser-Arg-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn- Asn-Xaa₅-Asp-Leu-Cys;(SEQ ID NO: 51) Xaa₅-Gln-Cys-Cys-Ser-His-Leu-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 52)Gly-Cys-Cys-Ser-Xaa₄-Phe-Asp-Cys-Arg-Met-Met-Phe-Xaa₅-Xaa₁-Met-Cys-Gly-Xaa₃-Arg; (SEQ ID NO: 53)Gly-Gly-Cys-Cys-Ser-Phe-Ala-Ala-Cys-Arg-Xaa₂-Xaa₄-Arg-Xaa₅-Xaa₁-Met-Cys-Gly; (SEQ ID NO: 54)Gly-Gly-Cys-Cys-Phe-His-Xaa₅-Val-Cys-Xaa₄-Ile-Asn-Leu-Leu-Xaa₁-Met-Cys-Arg-Gln-Arg; (SEQ ID NO: 55)Ser-Ala-Thr-Cys-Cys-Asn-Xaa₄-Xaa₅-Xaa₅-Cys-Xaa₄-Xaa₁-Thr-Xaa₄-Xaa₅-Xaa₁-Ser-Cys-Leu; (SEQ ID NO: 56)Ala-Cys-Cys-Ala-Xaa₄-Xaa₅-Xaa₅-Cys-Phe-Xaa₁-Ala-Xaa₄-Xaa₅-Xaa₁-Arg-Cys-Leu; (SEQ ID NO: 57)Asn-Ala-Xaa₁-Cys-Cys-Xaa₄-Xaa₄-Xaa₅-Xaa₅-Cys-Xaa₄-Xaa₁-Ala-Xaa₄-Xaa₅-Xaa₁-Ile-Cys-Leu; (SEQ ID NO: 170)Xaa₁-Cys-Cys-Thr-Asn-Xaa₅-Val-Cys-His-Ala-Xaa₁-His-Gln-Xaa₁-Leu-Cys-Ala-Arg-Arg-Arg; (SEQ ID NO: 171)Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Leu-Xaa₁- His-Ser-Asn-Leu-Cys;(SEQ ID NO: 172) Xaa₁-Cys-Cys-Thr-Asn-Xaa₅-Val-Cys-His-Val-Xaa₁-His-Gln-Xaa₁-Leu-Cys-Ala-Arg-Arg-Arg; (SEQ ID NO: 173)Xaa₆-Xaa₁-Cys-Cys-Ser-Xaa₄-Xaa₅-Ala-Cys-Asn-Leu-Asp-His-Xaa₅-Xaa₁-Leu-Cys; (SEQ ID NO: 174)Xaa₅-Xaa₁-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Ser-Thr-His-Xaa5-Xaa₁-Leu-Cys-Gly; (SEQ ID NO: 175)Leu-Asn-Cys-Cys-Met-Ile-Xaa₅-Xaa₅-Cys-Xaa₃-Xaa₂-Xaa₂-Xaa₄-Gly-Asp-Arg-Cys-Ser-Xaa₁-Val-Arg; (SEQ ID NO: 176)Ala-Phe-Gly-Cys-Cys-Asp-Leu-Ile-Xaa₅-Cys-Leu-Xaa₁-Arg-Xaa₄-Gly-Asn-Arg-Cys-Asn-Xaa₁-Val-His; (SEQ ID NO: 177)Leu-Gly-Cys-Cys-Asn-Val-Thr-Xaa₅-Cys-Xaa₃-Xaa₁-Xaa₂-Xaa₄-Gly-Asp-Xaa₂-Cys-Asn-Xaa₁-Val-Arg; (SEQ ID NO: 178)Asp-Xaa₁-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Arg-Val-Asn-Asn-Xaa₅-His-Val-Cys-Arg-Arg-Arg; (SEQ ID NO: 179)Leu-Asn-Cys-Cys-Ser-Ile-Xaa₅-Gly-Cys-Xaa₃-Asn-Xaa₁-Xaa₄-Xaa₂-Asp-Arg-Cys-Ser-Xaa₂-Val-Arg; (SEQ ID NO: 180)Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Xaa₄-Phe-Asn-Asn-Xaa₅-Gln-Met-Cys-Arg; (SEQ ID NO: 181)Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Asn-Leu-Asn-Asn-Xaa₅-Gln-Met-Cys-Arg; (SEQ ID NO: 182)Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Xaa₄-Ala-Asn-Asn-Gln-Ala-Xaa₄-Cys-Asn; (SEQ ID NO: 183)Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Val- Thr-His-Xaa₅-Xaa₁-Leu-Cys;(SEQ ID NO: 184) Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Ala-Cys-Ser-Val-Xaa₁-His-Gln-Asp-Leu-Cys-Asp; (SEQ ID NO: 185)Val-Ser-Cys-Cys-Val-Val-Arg-Xaa₅-Cys-Xaa₃-Ile-Arg-Xaa₄-Gln-Xaa₁-Xaa₁-Cys-Leu-Xaa₁-Ala-Asp- Xaa₅-Arg-Thr-Leu;(SEQ ID NO: 186) Xaa₆-Asn-Cys-Cys-Ser-Ile-Xaa₅-Gly-Cys-Xaa₃-Xaa₁-Xaa₂-Xaa₄-Gly-Asp-Xaa₂-Cys-Ser-Xaa₁-Val-Arg; (SEQ ID NO: 187)Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Leu-Xaa₁- His-Xaa₅-Asn-Ala-Cys;(SEQ ID NO: 188) Gly-Cys-Cys-Ser-Asn-Xaa₅-Ile-Cys-Xaa₄-Phe-Asn-Asn-Xaa₅-Arg-Ile-Cys-Arg; (SEQ ID NO: 189)Xaa₁-Cys-Cys-Ser-Gln-Xaa₅-Xaa₅-Cys-Arg-Xaa₃-Xaa₂-His-Xaa₅-Xaa₁-Leu-Cys-Ser; (SEQ ID NO: 190)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn- Asn-Gln-His-Ile-Cys;(SEQ ID NO: 191) Gly-Cys-Cys-Ala-Val-Xaa₅-Ser-Cys-Arg-Leu-Arg-Asn-Xaa₅-Asp-Leu-Cys-Gly-Gly; (SEQ ID NO: 192)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asn- Asn-Xaa₅-His-Ile-Cys;(SEQ ID NO: 193) Thr-Xaa₅-Xaa₁-Xaa₁-Cys-Cys-Xaa₅-Asn-Xaa₅-Xaa₅-Cys-Phe-Ala-Thr-Asn-Ser-Asp-Ile-Cys-Gly; (SEQ ID NO: 194)Asp-Ala-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Gly- Xaa₂-His-Gln-Asp-Leu-Cys;(SEQ ID NO: 195) Xaa₁-Asp-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Leu-Cys; (SEQ ID NO: 196)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Ser- Asn-Ala-His-Ile-Cys;(SEQ ID NO: 197) Xaa₁-Asp-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys; (SEQ ID NO: 198)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn- Asn-Xaa₅-His-Ile-Cys;(SEQ ID NO: 199) Gly-Cys-Cys-Gly-Asn-Xaa₅-Ser-Cys-Ser-Ile-His-Ile-Xaa₅-Xaa₄-Val-Cys-Asn; (SEQ ID NO: 200)Thr-Asp-Ser-Xaa₁-Xaa₁-Cys-Cys-Leu-Asp-Ser-Arg-Cys-Ala-Gly-Gln-His-Gln-Asp-Leu-Cys-Gly; (SEQ ID NO: 201)Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Xaa₄-Ala-Asn-Asn-Gln-Ala-Xaa₄-Cys-Asn; (SEQ ID NO: 202)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Val-Asn- Asn-Xaa₅-Asp-Ile-Cys;(SEQ ID NO: 203) Gly-Xaa₂-Cys-Cys-Ile-Asn-Asp-Ala-Cys-Arg-Ser-Xaa₂-His-Xaa₅-Gln-Xaa₄-Cys-Ser; (SEQ ID NO: 204)Gly-Cys-Cys-Xaa₄-Asn-Ile-Ala-Cys-Arg-Ile-Asn- Asn-Xaa₅-Arg-Xaa₄-Cys-Arg;Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Arg-Phe-Asn-Xaa₄-Xaa₅-Xaa₂-Xaa₄-Cys-Gly; (SEQ ID NO: 206)Asp-Xaa₁-Cys-Cys-Ala-Ser-Xaa₅-Xaa₅-Cys-Arg-Leu-Asn-Asn-Xaa₅-Xaa₄-Val-Cys-His; (SEQ ID NO: 207)Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Xaa₃-Gln-Asn-Asn-Ala-Xaa₁-Xaa₄-Cys-Arg-Xaa₁-Ser; (SEQ ID NO: 208)Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Ala-Gln-Asn- Asn-Gln-Asp-Xaa₄-Cys;(SEQ ID NO: 209) Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Arg-Xaa₁-Xaa₄-Cys-Arg-Xaa₁-Ser; (SEQ ID NO: 210)Asp-Xaa₅-Cys-Cys-Ser-Xaa₄-Xaa₅-Asp-Cys-Gly-Ala-Asn-His-Xaa₅-Xaa₁-Ile-Cys-Gly; (SEQ ID NO: 211)Xaa₁-Cys-Cys-Ser-Gln-Xaa₅-Xaa₅-Cys-Arg-Xaa₃-Xaa₂-His-Xaa₅-Xaa₁-Leu-Cys-Ser; (SEQ ID NO: 212)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn- Asn-Xaa₅-His-Ile-Cys;(SEQ ID NO: 213) Gly-Cys-Cys-Ser-Asp-Xaa₅-Ser-Cys-Asn-Val-Asn-Asn-Xaa₅-Asp-Xaa₄-Cys; (SEQ ID NO: 214)Xaa₁-Xaa₁-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys-Arg; (SEQ ID NO: 215)Gly-Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Leu-Val- Asn-His-Leu-Xaa₁-Met-Cys;(SEQ ID NO: 216) Arg-Asp-Xaa₅-Cys-Cys-Phe-Asn-Xaa₅-Ala-Cys-Asn-Val-Asn-Asn-Xaa₅-Gln-Ile-Cys; (SEQ ID NO: 217)Cys-Cys-Ser-Asp-Xaa₅-Ser-Cys-Xaa₃-Arg-Leu-His-Ser-Leu-Ala-Cys-Thr-Gly-Ile-Val-Asn-Arg; (SEQ ID NO: 218)Cys-Cys-Thr-Asn-Xaa₅-Ala-Cys-Leu-Val-Asn-Asn- Ile-Arg-Phe-Cys-Gly;(SEQ ID NO: 219) Asp-Xaa₁-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-His-Gly-Asn-Asn-Arg-Asp-His-Cys-Ala; (SEQ ID NO: 220)Asp-Cys-Cys-Ser-His-Xaa₅-Leu-Cys-Arg-Leu-Phe- Val-Xaa₅-Gly-Leu-Cys-Ile;(SEQ ID NO: 221) Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Xaa₂-Val-Arg-Xaa₄-Xaa₅-Asp-Leu-Cys-Arg; (SEQ ID NO: 222)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asn- Asn-Xaa₅-His-Ile-Cys;(SEQ ID NO: 223) Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Xaa₂-Val-Arg-Xaa₄-Ser-Asp-Met-Cys; (SEQ ID NO: 224)Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Xaa₂-Val- His-Phe-Xaa₅-His-Ser-Cys;(SEQ ID NO: 225) Val-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Val-Asp-His-Xaa₅-Xaa₁-Leu-Cys-Arg-Arg-Arg-Arg; (SEQ ID NO: 226)Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Asn-Leu-Ser- Asn-Xaa₅-Gln-Ile-Cys-Arg;(SEQ ID NO: 227) Xaa₆-Xaa₁-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 228)Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Leu-Val-Asn- His-Ile-Arg-Phe-Cys-Gly;(SEQ ID NO: 229) Asp-Cys-Cys-Asp-Asp-Xaa₅-Ala-Cys-Thr-Val-Asn-Asn-Xaa₅-Gly-Leu-Cys-Thr; and (SEQ ID NO: 230)Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ile-Ala-Xaa₂-Asn-Xaa₅-His-Met-Cys-Gly-Gly-Arg-Arg,wherein Xaa₁ is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys,N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Trp (D or L), halo-Trpor neo-Trp; Xaa₄ is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ is Pro orhydroxy-Pro; Xaa₆ is Gln or pyro-Glu; and the C-terminus contains acarboxyl or amide group. The halo is preferably bromine, chlorine oriodine, more preferably iodine for Tyr and bromine for Trp. In addition,the His residues may be substituted with halo-His; the Arg residues maybe substituted by Lys, ornithine, homoarginine, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid;the Lys residues may be substituted by Arg, ornithine, homoarginine,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; the Tyr residues may be substituted with any unnaturalhydroxy containing amino acid; the Ser residues may be substituted withThr; the Thr residues may be substituted with Ser; and the Phe and Trpresidues may be substituted with any unnatural aromatic amino acid. TheCys residues may be in D or L configuration and may optionally besubstituted with homocysteine (D or L). The Tyr residues may besubstituted with the 3-hydroxyl or 2-hydroxyl isomers and correspondingO-sulpho- and O-phospho-derivatives. The acidic amino acid residues maybe substituted with any synthetic acidic bioisoteric amino acidsurrogate, e.g., tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to the followingα-conotoxin peptides of general formula III:

SmI: SEQ ID NO: 22, wherein Xaa₁ is Glu and Xaa₅ is Pro; OB-29: SEQ IDNO: 23, wherein Xaa₁ is Glu, Xaa₃ is Tyr and Xaa₅ is Pro; Tx1.1: SEQ IDNO: 24, wherein Xaa₁ is Glu and Xaa₅ is Pro; R1.1A: SEQ ID NO: 25,wherein Xaa₁ is Glu and Xaa₅ is Pro; R1.1B: SEQ ID NO: 26, wherein Xaa₁is Glu and Xaa₅ is Pro; Om-9: SEQ ID NO: 27, wherein Xaa₁ is Glu andXaa₅ is Pro; Om-10: SEQ ID NO: 28, wherein Xaa₅ is Pro; Om-21: SEQ IDNO: 29, wherein Xaa₁ is Glu and Xaa₅ is Pro; Om-25: SEQ ID NO: 30,wherein Xaa₁ is Glu and Xaa₅ is Pro; Om-27: SEQ ID NO: 31, wherein Xaa₁is Glu and Xaa₅ is Pro; Om-28: SEQ ID NO: 32, wherein Xaa₁ is Glu andXaa₅ is Pro; Bt1.2: SEQ ID NO: 33, wherein Xaa₁ is Glu and Xaa₅ is Pro;Bt1.4: SEQ ID NO: 34, wherein Xaa₁ is Glu and Xaa₅ is Pro; Da1.1: SEQ IDNO: 35, wherein Xaa₁ is Glu and Xaa₅ is Pro; OB-20: SEQ ID NO: 36,wherein Xaa₁ is Glu, Xaa₂ is Lys and Xaa₅ is Pro; TI: SEQ ID NO: 37,wherein Xaa₁ is Glu and Xaa₅ is Pro; TIB: SEQ ID NO: 38, wherein Xaa₁ isGlu and Xaa₅ is Pro; Pn1.1: SEQ ID NO: 39, wherein Xaa₅ is Pro; Pn1.2:SEQ ID NO: 40, wherein Xaa₁ is Glu and Xaa₅ is Pro; T1: SEQ ID NO: 41,wherein Xaa₂ is Lys and Xaa₅ is Pro; TIA: SEQ ID NO: 43, wherein Xaa₅ isPro; Da1.2: SEQ ID NO: 44, wherein Xaa₅ is Pro; Cr1.2: SEQ ID NO: 45,wherein Xaa₁ is Glu and Xaa₅ is Pro; Sl1.2: SEQ ID NO: 46, wherein Xaa₁is Glu, Xaa₂ is Lys and Xaa₅ is Pro; Tx1.3: SEQ ID NO: 47, wherein Xaa₁is Glu and Xaa₅ is Pro; Da1.3: SEQ ID NO: 48, wherein Xaa₁ is Glu andXaa₅ is Pro; Da1.4: SEQ ID NO: 49, wherein Xaa₁ is Glu, Xaa₅ is Pro andXaa₆ is Gln; Tx1.2: SEQ ID NO: 50, wherein Xaa₅ is Pro; Om-35: SEQ IDNO: 51, wherein Xaa₁ is Glu and Xaa₅ is Pro; Sl1.1: SEQ ID NO: 52,wherein Xaa₁ is Glu, Xaa₃ is Trp, Xaa₄ is Tyr and Xaa₅ is Pro; Sl1.6:SEQ ID NO: 53, wherein Xaa₁ is Glu, Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ isPro; Sl1.7: SEQ ID NO: 54, wherein Xaa₁ is Glu Xaa₄ is Tyr and Xaa₅ isPro; Bt1.1: SEQ ID NO: 55, wherein Xaa₁ is Glu Xaa₄ is Tyr and Xaa₅ isPro; Bt: 1.3: SEQ ID NO: 56, wherein Xaa₁ is Glu Xaa₄ is Tyr and Xaa₅ isPro; Bt1.5: SEQ ID NO: 57, wherein Xaa₁ is Glu Xaa₄ is Tyr and Xaa₅ isPro; A1.4: SEQ ID NO: 170, wherein Xaa₁ is Glu and Xaa₅ is Pro; A1.5:SEQ ID NO: 171, wherein Xaa₁ is Glu and Xaa₅ is Pro; A1.6: SEQ ID NO:172, wherein Xaa₁ is Glu and Xaa₅ is Pro; Af1.1: SEQ ID NO: 173, whereinXaa₁ is Glu Xaa₄ is Tyr, Xaa₅ is Pro and Xaa₆ is Gln; Af1.2: SEQ ID NO:174, wherein Xaa₁ is Glu and Xaa₅ is Pro; Ar1.2: SEQ ID NO: 175, whereinXaa₁ is Glu, Xaa₂ is Lys, Xaa₃ is Trp, Xaa₄ is Try and Xaa₅ is Pro;Ar1.3: SEQ ID NO: 176, wherein Xaa₁ is Glu, Xaa₄ is Tyr and Xaa₅ is Pro;Ar1.4: SEQ ID NO: 177, wherein Xaa₁ is Glu, Xaa₂ is Lys, Xaa₃ is Trp,Xaa₄ is Try and Xaa₅ is Pro; Ar1.5: SEQ ID NO: 178, wherein Xaa₁ is Gluand Xaa₅ is Pro; Ar1.6: SEQ ID NO: 179, wherein Xaa₁ is Glu, Xaa₂ isLys, Xaa₃ is Trp, Xaa₄ is Try and Xaa₅ is Pro; Ay1.2: SEQ ID NO: 180,wherein Xaa₄ is Tyr and Xaa₅ is Pro; Ay1.3: SEQ ID NO: 181, wherein Xaa₅is Pro; Bn1.4: SEQ ID NO: 182, wherein Xaa₄ is Tyr and Xaa₅ is Pro;Bt1.8: SEQ ID NO: 183, wherein Xaa₁ is Glu and Xaa₅ is Pro; Bt1.9: SEQID NO: 184, wherein Xaa₁ is Glu, Xaa₄ is Tyr and Xaa₅ is Pro; Ca1.3: SEQID NO: 185, wherein Xaa₁ is Glu, Xaa₃ is Trp, Xaa₄ is Try and Xaa₅ isPro; Ca1.4: SEQ ID NO: 186, wherein Xaa₁ is Glu, Xaa₂ is Lys, Xaa₃ isTrp, Xaa₄ is Try, Xaa₅ is Pro and Xaa₆ is Gln; C1.2: SEQ ID NO: 187,wherein Xaa₁ is Glu and Xaa₅ is Pro; C1.3: SEQ ID NO: 188, wherein Xaa₄is Tyr and Xaa₅ is Pro; Ep1.2: SEQ ID NO: 189, wherein Xaa₁ is Glu, Xaa₂is Lys, Xaa₃ is Trp and Xaa₅ is Pro; G1.1: SEQ ID NO: 190, wherein Xaa₅is Pro; G1.3: SEQ ID NO: 191, wherein Xaa₅ is Pro; Im1.3: SEQ ID NO:192, wherein Xaa₅ is Pro; Lv1.2: SEQ ID NO: 193, wherein Xaa₁ is Glu andXaa₅ is Pro; Lv1.3: SEQ ID NO: 194, wherein Xaa₂ is Lys and Xaa₅ is Pro;Lv1.4: SEQ ID NO: 195, wherein Xaa₁ is Glu and Xaa₅ is Pro; Lv1.6: SEQID NO: 196, wherein Xaa₅ is Pro; Lv1.7: SEQ ID NO: 197, wherein Xaa₁ isGlu and Xaa₅ is Pro; Lv1.8: SEQ ID NO: 198, wherein Xaa₅ is Pro; Lv1.9:SEQ ID NO: 199, wherein Xaa₄ is Tyr and Xaa₅ is Pro; Lv1.10: SEQ ID NO:200, wherein Xaa₁ is Glu; Mr1.3: SEQ ID NO: 201, wherein Xaa₄ is Tyr andXaa₅ is Pro; Mr1.4: SEQ ID NO: 202, wherein Xaa₅ is Pro; Ms1.1: SEQ IDNO: 203, wherein Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro; Ms1.6: SEQ IDNO: 204, wherein Xaa₄ is Tyr and Xaa₅ is Pro; O1.1: SEQ ID NO: 205,wherein Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro; O1.2: SEQ ID NO: 206,wherein Xaa₁ is Glu, Xaa₄ is Tyr and Xaa₅ is Pro; O1.4: SEQ ID NO: 207,wherein Xaa₁ is Glu, Xaa₃ is Trp, Xaa₄ is Tyr and Xaa₅ is Pro; O1.7: SEQID NO: 208, wherein Xaa₄ is Tyr and Xaa₅ is Pro; O1.8: SEQ ID NO: 209,wherein Xaa₁ is Glu, Xaa₄ is Tyr and Xaa₅ is Pro; Om1.2: SEQ ID NO: 210,wherein Xaa₁ is Glu, Xaa₄ is Tyr and Xaa₅ is Pro; Om1.3: SEQ ID NO: 211,wherein Xaa₁ is Glu, Xaa₂ is Lys, Xaa₃ is Trp and Xaa₅ is Pro; Om1.4:SEQ ID NO: 212, wherein Xaa₅ is Pro; Om1.5: SEQ ID NO: 213, wherein Xaa₄is Tyr and Xaa₅ is Pro; Om1.6: SEQ ID NO: 214, wherein Xaa₁ is Glu andXaa₅ is Pro; P1.4: SEQ ID NO: 215, wherein Xaa₁ is Glu and Xaa₅ is Pro;P1.5: SEQ ID NO: 216, wherein Xaa₅ is Pro; P1.6: SEQ ID NO: 217, whereinXaa₃ is Trp and Xaa₅ is Pro; P1.8: SEQ ID NO: 218, wherein Xaa₅ is Pro;Rg1.1: SEQ ID NO: 219, wherein Xaa₁ is Glu and Xaa₅ is Pro; Rg1.3: SEQID NO: 220, wherein Xaa₅ is Pro; Rg1.4: SEQ ID NO: 221, wherein Xaa₂ isLys, Xaa₄ is Tyr and Xaa₅ is Pro; Rg1.5: SEQ ID NO: 222, wherein Xaa₅ isPro; Rg1.8: SEQ ID NO: 223, wherein Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ isPro; Sm1.4: SEQ ID NO: 224, wherein Xaa₂ is Lys and Xaa₅ is Pro; Sm1.5:SEQ ID NO: 225, wherein Xaa₁ is Glu and Xaa₅ is Pro; S1.5: SEQ ID NO:226, wherein Xaa₅ is Pro; Tx1.5: SEQ ID NO: 227, wherein Xaa₁ is Glu,Xaa₅ is Pro and Xaa₆ is Gln; T1.1: SEQ ID NO: 228, wherein Xaa₅ is Pro;Vr1.3: SEQ ID NO: 229, wherein Xaa₅ is Pro; and Tb: SEQ ID NO: 230,wherein Xaa₂ is Lys and Xaa₅ is Pro.The C-terminus preferably contains a carboxyl group for the peptidesOB-29, Tx1.1, R1.1A, R1.1B, Om-9, Om-10, Om-21, Om-25, Om-27, Om-28,Cr1.2, Om-35, Bt1.1, Bt1.3, Bt1.5, A1.4, A1.6, Ar1.2, Ar1.3, Ar1.4,Ar1.5, Ar1.6, Ca1.3, Ca1.4, Ep1.2, Lv1.9, O1.2, Om1.3, Om1.6, P1.6,Rg1.1, Rg1.3, Rg1.4, Sm1.5, Tx1.5 and Vr1.3. The C-terminus of the otherpeptides preferably contains an amide group.

The present invention is also directed to the novel specific α-conotoxinpeptides having the formulas:

(SEQ ID NO: 231) Cys-Cys-Thr-Ile-Xaa₅-Ser-Cys-Xaa₄-Xaa₁-Xaa₂-Xaa₂-Xaa₂-Ile-Xaa₂-Ala-Cys-Val-Phe and (SEQ ID NO: 232)Gly-Cys-Cys-Gly-Asn-Xaa₅-Ala-Cys-Ser-Gly-Ser-Ser-Xaa₂-Asp-Ala-Xaa₅-Ser-Cys,wherein Xaa₁ is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys,N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₄ is Tyr, nor-Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr;and Xaa₅ is Pro or hydroxy-Pro; and the C-terminus contains a carboxylor amide group. The halo is preferably bromine, chlorine or iodine, morepreferably iodine for Tyr. In addition, the His residues may besubstituted with halo-His; the Arg residues may be substituted by Lys,ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys,N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Lys residuesmay be substituted by Arg, ornithine, homoarginine, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid;the Tyr residues may be substituted with any unnatural hydroxycontaining amino acid; the Ser residues may be substituted with Thr; theThr residues may be substituted with Ser; and the Phe residues may besubstituted with any unnatural aromatic amino acid. The Cys residues maybe in D or L configuration and may optionally be substituted withhomocysteine (D or L). The Tyr residues may be substituted with the3-hydroxyl or 2-hydroxyl isomers and corresponding O-sulpho- andO-phospho-derivatives. The acidic amino acid residues may be substitutedwith any synthetic acidic bioisoteric amino acid surrogate, e.g.,tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to the followingα-conotoxin peptides:

G1.2: SEQ ID NO: 231, wherein Xaa₁ is Glu, Xaa₂ is Lys, Xaa₄ is Tyr andXaa₅ is Pro; and Rg1.12: SEQ ID NO: 232, wherein Xaa₂ is Lys and Xaa₅ isPro.The C-terminus of G1.2 preferably contains a carboxyl group, and theC-terminus of Rg1.12 preferably contains an amide group.

Examples of unnatural aromatic amino acid include, but are not limitedto, such as nitro-Phe, 4-substituted-Phe wherein the substituent isC₁-C₃ alkyl, carboxyl, hydroxymethyl, sulphomethyl, halo, phenyl, —CHO,—CN, —SO₃H and —NHAc. Examples of unnatural hydroxy containing aminoacid, include, but are not limited to, such as 4-hydroxymethyl-Phe,4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr. Examples ofunnatural basic amino acids include, but are not limited to,N-1-(2-pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly, 2-(4-piperinyl)-Ala,2-[3-(2S)pyrrolininyl)-Gly and 2-[3-(2S)pyrrolininyl)-Ala. These andother unnatural basic amino acids, unnatural hydroxy containing aminoacids or unnatural aromatic amino acids are described in Building BlockIndex, Version 3.0 (1999 Catalog, pages 4-47 for hydroxy containingamino acids and aromatic amino acids and pages 66-87 for basic aminoacids; see also website “amino-acids.com”), incorporated herein byreference, by and available from RSP Amino Acid Analogues, Inc.,Worcester, Mass.

Optionally, in the peptides of general formulas I, II and III and thespecific peptides described above, the Asn residues may be modified tocontain an N-glycan and the Ser and Thr residues may be modified tocontain an O-glycan. In accordance with the present invention, a glycanshall mean any N-, S- or O-linked mono-, di-, tri-, poly- oroligosaccharide that can be attached to any hydroxy, amino or thiolgroup of natural or modified amino acids by synthetic or enzymaticmethodologies known in the art. The monosaccharides making up the glycancan include D-allose, D-altrose, D-glucose, D-mannose, D-gulose,D-idose, D-galactose, D-talose, D-galactosamine, D-glucosamine,D-N-acetyl-glucosamine (G1cNAc), D-N-acetyl-galactosamine (GalNAc),D-fucose or D-arabinose. These saccharides may be structurally modified,e.g., with one or more O-sulfate, O-phosphate, O-acetyl or acidicgroups, such as sialic acid, including combinations thereof. The glycanmay also include similar polyhydroxy groups, such as D-penicillamine 2,5and halogenated derivatives thereof or polypropylene glycol derivatives.The glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3. Thelinkage between the glycan and the amino acid may be alpha or beta,preferably alpha and is 1-.

Core O-glycans have been described by Van de Steen et al. (1998),incorporated herein by reference. Mucin type O-linked oligosaccharidesare attached to Ser or Thr (or other hydroxylated residues of thepresent peptides) by a GalNAc residue. The monosaccharide buildingblocks and the linkage attached to this first GalNAc residue define the“core glycans,” of which eight have been identified. The type ofglycosidic linkage (orientation and connectivities) are defined for eachcore glycan. Suitable glycans and glycan analogs are described furtherin U.S. Ser. No. 09/420,797, filed 19 Oct. 1999 (now U.S. Pat. No.6,369,193) and in PCT Application No. PCT/US99/24380, filed 19 Oct.1999, both incorporated herein by reference. A preferred glycan isGal(β1→3)GalNAc(α1→).

Optionally, in the peptides of general formulas I and II and thespecific peptides described above, pairs of Cys residues may be replacedpairwise with Ser/(Glu or Asp) or Lys/(Glu or Asp) combinations.Sequential coupling by known methods (Barnay et al., 2000; Hruby et al.,1994; Bitan et al., 1997) allows replacement of native Cys bridges withlactam bridges.

The present invention is further directed to propeptides and nucleicacid sequences encoding the propeptides or peptides as described infurther detail herein.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to relatively short peptides (termed α-conotoxinsherein), about 10-30 residues in length, which are naturally availablein minute amounts in the venom of the cone snails or analogous to thenaturally available peptides, and which preferably include two disulfidebonds.

The present invention, in another aspect, relates to a pharmaceuticalcomposition comprising an effective amount of an α-conotoxin peptide.Such a pharmaceutical composition has the capability of acting asantagonists for nicotinic acetylcholine receptors. In one aspect, theα-conotoxins with specificity for neuromuscular junction nicotinicacetylcholine receptors are used as neuromuscular blocking agents foruse in conjunction with surgery, as disclosed in U.S. patent applicationSer. No. 09/488,799, filed 21 Jan. 2000, incorporated by referenceherein. In a second aspect, additional α-conotoxins and uses for themhave been described in U.S. Pat. Nos. 4,447,356 (Olivera et al., 1984);5,432,155; 5,514,774, each incorporated herein by reference.

In a third aspect additional uses for α-conotoxins are described in U.S.Ser. No. 09/219,446, filed 22 Dec. 1998, incorporated herein byreference. In this application, a-conotoxins with specificity forneuronal nicotinic acetylcholine receptors are used for treatingdisorders regulated at neuronal nicotinic acetylcholine receptors. Suchdisorders include, but are not limited to, cardiovascular disorders,gastric motility disorders, urinary incontinence, nicotine addiction,mood disorders (such as bipolar disorder, unipolar depression, dysthymiaand seasonal effective disorder) and small cell lung carcinoma, as wellas the localization of small cell lung carcinoma.

The α-conotoxin peptides described herein are sufficiently small to bechemically synthesized. General chemical syntheses for preparing theforegoing α-conotoxin peptides are described hereinafter. Various onesof the α-conotoxin peptides can also be obtained by isolation andpurification from specific Conus species using the technique describedin U.S. Pat. No. 4,447,356 (Olivera et al., 1984), the disclosure ofwhich is incorporated herein by reference.

Although the α-conotoxin peptides of the present invention can beobtained by purification from cone snails, because the amounts ofα-conotoxin peptides obtainable from individual snails are very small,the desired substantially pure α-conotoxin peptides are best practicallyobtained in commercially valuable amounts by chemical synthesis usingsolid-phase strategy. For example, the yield from a single cone snailmay be about 10 micrograms or less of α-conotoxin peptide. By“substantially pure” is meant that the peptide is present in thesubstantial absence of other biological molecules of the same type; itis preferably present in an amount of at least about 85% purity andpreferably at least about 95% purity. Chemical synthesis of biologicallyactive α-conotoxin peptides depends of course upon correct determinationof the amino acid sequence.

The α-conotoxin peptides can also be produced by recombinant DNAtechniques well known in the art. Such techniques are described bySambrook et al. (1989). The peptides produced in this manner areisolated, reduced if necessary, and oxidized to form the correctdisulfide bonds.

One method of forming disulfide bonds in the conantokin peptides of thepresent invention is the air oxidation of the linear peptides forprolonged periods under cold room temperatures or at room temperature.This procedure results in the creation of a substantial amount of thebioactive, disulfide-linked peptides. The oxidized peptides arefractionated using reverse-phase high performance liquid chromatography(HPLC) or the like, to separate peptides having different linkedconfigurations. Thereafter, either by comparing these fractions with theelution of the native material or by using a simple assay, theparticular fraction having the correct linkage for maximum biologicalpotency is easily determined However, because of the dilution resultingfrom the presence of other fractions of less biopotency, a somewhathigher dosage may be required.

The peptides are synthesized by a suitable method, such as byexclusively solid-phase techniques, by partial solid-phase techniques,by fragment condensation or by classical solution couplings.

In conventional solution phase peptide synthesis, the peptide chain canbe prepared by a series of coupling reactions in which constituent aminoacids are added to the growing peptide chain in the desired sequence.Use of various coupling reagents, e.g., dicyclohexylcarbodiimide ordiisopropylcarbonyldimidazole, various active esters, e.g., esters ofN-hydroxyphthalimide or N-hydroxy-succinimide, and the various cleavagereagents, to carry out reaction in solution, with subsequent isolationand purification of intermediates, is well known classical peptidemethodology. Classical solution synthesis is described in detail in thetreatise, “Methoden der Organischen Chemie (Houben-Weyl): Synthese vonPeptiden,” (1974). Techniques of exclusively solid-phase synthesis areset forth in the textbook, “Solid-Phase Peptide Synthesis,” (Stewart andYoung, 1969), and are exemplified by the disclosure of U.S. Pat. No.4,105,603 (Vale et al., 1978). The fragment condensation method ofsynthesis is exemplified in U.S. Pat. No. 3,972,859 (1976). Otheravailable syntheses are exemplified by U.S. Pat. No. 3,842,067 (1974)and 3,862,925 (1975). The synthesis of peptides containingγ-carboxyglutamic acid residues is exemplified by Rivier et al. (1987),Nishiuchi et al. (1993) and Zhou et al. (1996).

Common to such chemical syntheses is the protection of the labile sidechain groups of the various amino acid moieties with suitable protectinggroups which will prevent a chemical reaction from occurring at thatsite until the group is ultimately removed. Usually also common is theprotection of an α-amino group on an amino acid or a fragment while thatentity reacts at the carboxyl group, followed by the selective removalof the α-amino protecting group to allow subsequent reaction to takeplace at that location. Accordingly, it is common that, as a step insuch a synthesis, an intermediate compound is produced which includeseach of the amino acid residues located in its desired sequence in thepeptide chain with appropriate side-chain protecting groups linked tovarious ones of the residues having labile side chains.

As far as the selection of a side chain amino protecting group isconcerned, generally one is chosen which is not removed duringdeprotection of the α-amino groups during the synthesis. However, forsome amino acids, e.g., His, protection is not generally necessary. Inselecting a particular side chain protecting group to be used in thesynthesis of the peptides, the following general rules are followed: (a)the protecting group preferably retains its protecting properties and isnot split off under coupling conditions, (b) the protecting group shouldbe stable under the reaction conditions selected for removing theα-amino protecting group at each step of the synthesis, and (c) the sidechain protecting group must be removable, upon the completion of thesynthesis containing the desired amino acid sequence, under reactionconditions that will not undesirably alter the peptide chain.

It should be possible to prepare many, or even all, of these peptidesusing recombinant DNA technology. However, when peptides are not soprepared, they are preferably prepared using the Merrifield solid-phasesynthesis, although other equivalent chemical syntheses known in the artcan also be used as previously mentioned. Solid-phase synthesis iscommenced from the C-terminus of the peptide by coupling a protectedα-amino acid to a suitable resin. Such a starting material can beprepared by attaching an α-amino-protected amino acid by an esterlinkage to a chloromethylated resin or a hydroxymethyl resin, or by anamide bond to a benzhydrylamine (BHA) resin or paramethylbenzhydrylamine(MBHA) resin. Preparation of the hydroxymethyl resin is described byBodansky et al. (1966). Chloromethylated resins are commerciallyavailable from Bio Rad Laboratories (Richmond, Calif.) and from Lab.Systems, Inc. The preparation of such a resin is described by Stewartand Young (1969). BHA and MBHA resin supports are commerciallyavailable, and are generally used when the desired polypeptide beingsynthesized has an unsubstituted amide at the C-terminus Thus, solidresin supports may be any of those known in the art, such as one havingthe formulae —O—CH₂-resin support, —NH BHA resin support, or —NH-MBHAresin support. When the unsubstituted amide is desired, use of a BHA orMBHA resin is preferred, because cleavage directly gives the amide. Incase the N-methyl amide is desired, it can be generated from an N-methylBHA resin. Should other substituted amides be desired, the teaching ofU.S. Pat. No. 4,569,967 (Kornreich et al., 1986) can be used, or shouldstill other groups than the free acid be desired at the C-terminus, itmay be preferable to synthesize the peptide using classical methods asset forth in the Houben-Weyl text (1974).

The C-terminal amino acid, protected by Boc or Fmoc and by a side-chainprotecting group, if appropriate, can be first coupled to achloromethylated resin according to the procedure set forth in K. Horikiet al. (1978), using KF in DMF at about 60° C. for 24 hours withstirring, when a peptide having free acid at the C-terminus is to besynthesized. Following the coupling of the BOC-protected amino acid tothe resin support, the α-amino protecting group is removed, as by usingtrifluoroacetic acid (TFA) in methylene chloride or TFA alone. Thedeprotection is carried out at a temperature between about 0° C. androom temperature. Other standard cleaving reagents, such as HCl indioxane, and conditions for removal of specific α-amino protectinggroups may be used as described in Schroder & Lubke (1965).

After removal of the α-amino-protecting group, the remaining α-amino-and side chain-protected amino acids are coupled step-wise in thedesired order to obtain the intermediate compound defined hereinbefore,or as an alternative to adding each amino acid separately in thesynthesis, some of them may be coupled to one another prior to additionto the solid phase reactor. Selection of an appropriate coupling reagentis within the skill of the art. Particularly suitable as a couplingreagent is N,N′-dicyclohexylcarbodiimide (DCC, DIC, HBTU, HATU, TBTU inthe presence of HoBt or HoAt).

The activating reagents used in the solid phase synthesis of thepeptides are well known in the peptide art. Examples of suitableactivating reagents are carbodiimides, such asN,N′-diisopropylcarbodiimide andN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide. Other activatingreagents and their use in peptide coupling are described by Schroder &Lubke (1965) and Kapoor (1970).

Each protected amino acid or amino acid sequence is introduced into thesolid-phase reactor in about a twofold or more excess, and the couplingmay be carried out in a medium of dimethylformamide (DMF):CH₂Cl₂ (1:1)or in DMF or CH₂Cl₂ alone. In cases where intermediate coupling occurs,the coupling procedure is repeated before removal of the α-aminoprotecting group prior to the coupling of the next amino acid. Thesuccess of the coupling reaction at each stage of the synthesis, ifperformed manually, is preferably monitored by the ninhydrin reaction,as described by Kaiser et al. (1970). Coupling reactions can beperformed automatically, as on a Beckman 990 automatic synthesizer,using a program such as that reported in Rivier et al. (1978).

After the desired amino acid sequence has been completed, theintermediate peptide can be removed from the resin support by treatmentwith a reagent, such as liquid hydrogen fluoride or TFA (if using Fmocchemistry), which not only cleaves the peptide from the resin but alsocleaves all remaining side chain protecting groups and also the α-aminoprotecting group at the N-terminus if it was not previously removed toobtain the peptide in the form of the free acid. If Met is present inthe sequence, the Boc protecting group is preferably first removed usingtrifluoroacetic acid (TFA)/ethanedithiol prior to cleaving the peptidefrom the resin with HF to eliminate potential S-alkylation. When usinghydrogen fluoride or TFA for cleaving, one or more scavengers such asanisole, cresol, dimethyl sulfide and methylethyl sulfide are includedin the reaction vessel.

Cyclization of the linear peptide is preferably affected, as opposed tocyclizing the peptide while a part of the peptido-resin, to create bondsbetween Cys residues. To effect such a disulfide cyclizing linkage,fully protected peptide can be cleaved from a hydroxymethylated resin ora chloromethylated resin support by ammonolysis, as is well known in theart, to yield the fully protected amide intermediate, which isthereafter suitably cyclized and deprotected. Alternatively,deprotection, as well as cleavage of the peptide from the above resinsor a benzhydrylamine (BHA) resin or a methylbenzhydrylamine (MBHA), cantake place at 0° C. with hydrofluoric acid (HF) or TFA, followed byoxidation as described above.

The peptides are also synthesized using an automatic synthesizer. Aminoacids are sequentially coupled to an MBHA Rink resin (typically 100 mgof resin) beginning at the C-terminus using an Advanced Chemtech 357Automatic Peptide Synthesizer. Couplings are carried out using1,3-diisopropylcarbodimide in N-methylpyrrolidinone (NMP) or by2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU) and diethyliso-propylethylamine (DIEA). The FMOC protecting groupis removed by treatment with a 20% solution of piperidine indimethylformamide(DMF). Resins are subsequently washed with DMF (twice),followed by methanol and NMP.

Pharmaceutical compositions containing a compound of the presentinvention or its pharmaceutically acceptable salts as the activeingredient can be prepared according to conventional pharmaceuticalcompounding techniques. See, for example, Remington's PharmaceuticalSciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa.). Typically,an antagonistic amount of the active ingredient will be admixed with apharmaceutically acceptable carrier. The carrier may take a wide varietyof forms depending on the form of preparation desired foradministration, e.g., intravenous, oral or parenteral. The compositionsmay further contain antioxidizing agents, stabilizing agents,preservatives and the like.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, lozenges, melts,powders, suspensions or emulsions. In preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed, suchas, for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, suspending agents, and the like in thecase of oral liquid preparations (such as, for example, suspensions,elixirs and solutions); or carriers such as starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike in the case of oral solid preparations (such as, for example,powders, capsules and tablets). Because of their ease in administration,tablets and capsules represent the most advantageous oral dosage unitform, in which case solid pharmaceutical carriers are obviouslyemployed. If desired, tablets may be sugar-coated or enteric-coated bystandard techniques. The active agent can be encapsulated to make itstable to passage through the gastrointestinal tract while at the sametime allowing for passage across the blood brain barrier. See forexample, WO 96/11698.

For parenteral administration, the compound may be dissolved in apharmaceutical carrier and administered as either a solution or asuspension. Illustrative of suitable carriers are water, saline,dextrose solutions, fructose solutions, ethanol, or oils of animal,vegetative or synthetic origin. The carrier may also contain otheringredients, for example, preservatives, suspending agents, solubilizingagents, buffers and the like. When the compounds are being administeredintrathecally, they may also be dissolved in cerebrospinal fluid.

The active agent is preferably administered in an therapeuticallyeffective amount. The actual amount administered, and the rate andtime-course of administration, will depend on the nature and severity ofthe condition being treated. Prescription of treatment, e.g. decisionson dosage, timing, etc., is within the responsibility of generalpractitioners or specialists, and typically takes account of thedisorder to be treated, the condition of the individual patient, thesite of delivery, the method of administration and other factors knownto practitioners. Examples of techniques and protocols can be found inRemington's Pharmaceutical Sciences. Typically the conopeptides of thepresent invention exhibit their effect at a dosage range from about0.001 mg/kg to about 250 mg/kg, preferably from about 0.05 mg/kg toabout 100 mg/kg of the active ingredient, more preferably from a bout0.1 mg/kg to about 75 mg/kg. A suitable dose can be administered inmultiple sub-doses per day. Typically, a dose or sub-dose may containfrom about 0.1 mg to about 500 mg of the active ingredient per unitdosage form. A more preferred dosage will contain from about 0.5 mg toabout 100 mg of active ingredient per unit dosage form. Dosages aregenerally initiated at lower levels and increased until desired effectsare achieved.

Alternatively, targeting therapies may be used to deliver the activeagent more specifically to certain types of cell, by the use oftargeting systems such as antibodies or cell specific ligands. Targetingmay be desirable for a variety of reasons, e.g. if the agent isunacceptably toxic, or if it would otherwise require too high a dosage,or if it would not otherwise be able to enter the target cells.

The active agents, which are peptides, can also be administered in acell based delivery system in which a DNA sequence encoding an activeagent is introduced into cells designed for implantation in the body ofthe patient, especially in the spinal cord region. Suitable deliverysystems are described in U.S. Pat. No. 5,550,050 and published PCTApplication Nos. WO 92/19195, WO 94/25503, WO 95/01203, WO 95/05452, WO96/02286, WO 96/02646, WO 96/40871, WO 96/40959 and WO 97/12635.Suitable DNA sequences can be prepared synthetically for each activeagent on the basis of the developed sequences and the known geneticcode.

EXAMPLES

The present invention is described by reference to the followingExamples, which are offered by way of illustration and are not intendedto limit the invention in any manner. Standard techniques well known inthe art or the techniques specifically described below were utilized.

Example 1 Isolation of α-Conotoxins

Crude venom was extracted from venom ducts (Cruz et al., 1976), and thecomponents were purified as previously described (Cartier et al.,1996a). The crude extract from venom ducts was purified by reverse phaseliquid chromatography (RPLC) using a Vydac C₁₈ semi-preparative column(10×250 mm) and elution with a linear gradient of acetonitrile in 0.1%TFA. Further purification of bioactive peaks was done on a Vydac C₁₈analytical column (4.6×220 mm) eluted with a gradient of acetonitrile in0.1% TFA. The effluents were monitored at 220 nm. Peaks were collected,and aliquots were assayed for activity. Activity was monitored byassessing block of α3β4 nAChRs expressed in Xenopus oocytes.

The amino acid sequence of the purified peptides were determined bystandard methods. The purified peptides were reduced and alkylated priorto sequencing by automated Edman degradation on an Applied Biosystems477A Protein Sequencer with a 120A Analyzer (DNA/Peptide Facility,University of Utah) (Martinez et al., 1995; Shon et al., 1994).

In accordance with this method, peptides MII, AuIA, AuIB, AuIC, MAR-1,MAR-2, TI, OB-29, EpI, S1.1, Bn1.1, Bn1.2, Ca1.1, Ca1.2, Cn1.1, Cn1.2and Sm1.3 were obtained.

Example 2 Synthesis of Conopeptides

The synthesis of conopeptides, either the mature toxins or the precursorpeptides, was separately performed using conventional protectionchemistry as described by Cartier et al. (1996). Briefly, the linearchains were built on Rink amide resin by Fmoc procedures with2-(1H-benzotriol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroboratedcoupling using an ABI model 430A peptide synthesizer with amino acidderivatives purchased from Bachem (Torrance Calif.). Orthogonalprotection was used on cysteines: Cys³ and Cys¹⁶ were protected as thestable Cys(S-acetamidomethyl), while Cys² and Cys⁸ were protected as theacid-labile Cys(S-trityl). After removal of the terminal Fmoc protectinggroup and cleavage of the peptides from the resins, the releasedpeptides were precipitated by filtering the reaction mixture into −10°C. methyl t-butyl ether, which removed the protecting groups except onCys³ and Cys¹⁶. The peptides were dissolved in 0.1% TFA and 60%acetonitrile and purified by RPLC on a Vydac C₁₈ preparative column(22×250 mm) and eluted at a flow rate of 20 mL/min with a gradient ofacetonitrile in 0.1% TFA.

The disulfide bridges in the three conopeptides were formed as describedin Cartier et al. (1996). Briefly, the disulfide bridges between Cys²and Cys⁸ were formed by air oxidation which was judged to be complete byanalytical RPLC. The monocyclic peptides were purified by RPLC on aVydac C₁₈ preparative column (22×250 mm) and eluted with a gradient ofacetonitrile in 0.1% TFA. Removal of S-acetamidomethyl groups andclosure of the disulfide bridge between Cys³ and Cys¹⁶ was carried outsimultaneously be iodine oxidation. The cyclic peptides were purified byRPLC on a Vydac C₁₈ preparative column (22×250 mm) and eluted with agradient of acetonitrile in 0.1% TFA.

Example 3 Isolation of DNA Encoding α-Conotoxins

DNA coding for α-conotoxins was isolated and cloned in accordance withconventional techniques using general procedures well known in the art,such as described in Olivera et al. (1996). Alternatively, cDNAlibraries was prepared from Conus venom duct using conventionaltechniques. DNA from single clones was amplified by conventionaltechniques using primers which correspond approximately to the M13universal priming site and the M13 reverse universal priming site.Clones having a size of approximately 300 nucleotides were sequenced andscreened for similarity in sequence to known α-conotoxins. The DNAsequences and encoded propeptide or peptide sequences are set forth inTables 1-134.

TABLE 1 DNA Sequence (SEQ ID NO: 58) and ProteinSequence (SEQ ID NO: 59) of MIIatg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr act gtc gtt tccThr Val Val Ser ttc cct tca gat cgt gca tct gat ggc agg aat gccPhe Pro Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala gca gcc aac gacAla Ala Asn Asp aaa gcg tct gac gtg atc acg ctg gcc ctc aag ggaLys Ala Ser Asp Val Ile Thr Leu Ala Leu Lys Gly tgc tgt tcc aacCys Cys Ser Asn cct gtc tgt cac ttg gag cat tca aac ctt tgt ggtPro Val Cys His Leu Glu His Ser Asn Leu Cys Gly aga aga cgc Arg Arg Argtgatgctcca ggaccctctg aaccacgacg ttcgagca

TABLE 2 DNA Sequence (SEQ ID NO: 60) andProtein Sequence (SEQ ID NO: 61) of AuIAatg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr acc gtc gtt tccThr Val Val Ser ttc act tca gat cgt gca tct gat ggc agg aag gacPhe Thr Ser Asp Arg Ala Ser Asp Gly Arg Lys Asp gca gcg tct ggcAla Ala Ser Gly ctg atc gct ctg acc atc aag gga tgc tgt tct tatLeu Ile Ala Leu Thr Ile Lys Gly Cys Cys Ser Tyr cct ccc tgt ttcPro Pro Cys Phe gcg act aat tca gac tat tgt ggt tgacgacgctAla Thr Asn Ser Asp Tyr Cys Gly gatgctccag gaccctctga accacgacgt

TABLE 3 DNA Sequence (SEQ ID NO: 62) andProtein Sequence (SEQ ID NO: 63) of AuIBatg ttc acc gtg ttt ctg ttg gtc gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr acc gtc gtt tccThr Val Val Ser ttc act tca gat cgt gca tct gat ggc agg aag gacPhe Thr Ser Asp Arg Ala Ser Asp Gly Arg Lys Asp gca gcg tct ggcAla Ala Ser Gly ctg att gct ctg acc atg aag gga tgc tgt tct tatLeu Ile Ala Leu Thr Met Lys Gly Cys Cys Ser Tyr cct ccc tgt ttcPro Pro Cys Phe gcg act aat cca gac tgt ggt cga cga cgcAla Thr Asn Pro Asp Cys Gly Arg Arg Argtgatgctcca ggaccctctg aaccacgacg t

TABLE 4  DNA Sequence (SEQ ID NO: 64) andProtein Sequence (SEQ ID NO: 65) of Tx1.3atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ttc tct tca ggt cgt agt aca tttThr Val Val Ser Phe Ser Ser Gly Arg Ser Thr Phecgt ggc agg aat gcc gca gcc aaa gcg tct ggc ctgArg Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leugtc agt ctg act gac agg aga cca gaa tgc tgt agtVal Ser Leu Thr Asp Arg Arg Pro Glu Cys Cys Sergat cct cgc tgt aac tcg agt cat cca gaa ctt tgtAsp Pro Arg Cys Asn Ser Ser His Pro Glu Leu Cysggt gga aga cgc tgatgctcca ggaccctctg aaccacgacg t Gly Gly Arg Arg

TABLE 5 DNA Sequence (SEQ ID NO: 66) andProtein Sequence (SEQ ID NO: 67) of Tx1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thrgcc gtc gtt tcc ttc act tca gat cgt gca tct gatAla Val Val Ser Phe Thr Ser Asp Arg Ala Ser Aspgac ggg aaa gcc get gcg tct gac ctg atc act ctgAsp Gly Lys Ala Ala Ala Ser Asp Leu Ile Thr Leuacc atc aag gga tgc tgt tct cgt cct ccc tgt atcThr Ile Lys Gly Cys Cys Ser Arg Pro Pro Cys Ilegcg aat aat cca gac ttg tgt ggt tgacgacgctAla Asn Asn Pro Asp Leu Cys Glygatgctccag aacggtctga accacgacgt tcgagcaatg ttcaccgtgt ttctgttggt tgtctt

TABLE 6 DNA Sequence (SEQ ID NO: 68) andProtein Sequence (SEQ ID NO: 69) of Tx1.1atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ttc act tca ggt cgt agt aca tttThr Val Val Ser Phe Thr Ser Gly Arg Ser Thr Phecgt ggc agg aat gcc gca gcc aaa gcg tct ggc ctgArg Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leugtc agt ctg act gac agg aga cca caa tgc tgt tctVal Ser Leu Thr Asp Arg Arg Pro Gln Cys Cys Sercat cct gcc tgt aac gta gat cat cca gaa att tgtHis Pro Ala Cys Asn Val Asp His Pro Glu Ile Cyscgt tgaagacgct gatgctccag gaccctctga accacgacgt Arg

TABLE 7 DNA Sequence (SEQ ID NO: 70) andProtein Sequence (SEQ ID NO: 71) of R1.1Aatg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ttc act tca ggt cgt cgt aca tttThr Val Val Ser Phe Thr Ser Gly Arg Arg Thr Phecat ggc agg aat gcc gca gcc aaa gcg tct ggc ctgHis Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leugtc agt ctg act gac agg aga cca gaa tgc tgt tctVal Ser Leu Thr Asp Arg Arg Pro Glu Cys Cys Sercat cct gcc tgt aac gta gat cat cca gaa att tgtHis Pro Ala Cys Asn Val Asp His Pro Glu Ile Cyscgt tgaagacgct gatgctccag gaccctctga accacgacgt Arg

TABLE 8 DNA Sequence (SEQ ID NO: 72) andProtein Sequence (SEQ ID NO: 73) of R1.1Batg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ttc act tca ggt cgt agt aca tttThr Val Val Ser Phe Thr Ser Gly Arg Ser Thr Phecgt ggc agg aat gcc gca gcc aaa gcg tct ggc ctgArg Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leugtc agt ctg act gac agg aga cca caa tgc tgt tctVal Ser Leu Thr Asp Arg Arg Pro Gln Cys Cys Sercat cct gcc tgt aac gta gat cat cca gaa att tgcHis Pro Ala Cys Asn Val Asp His Pro Glu Ile Cysgat tgaagacgct gatgctccag gaccctctga accacgacgt Asp

TABLE 9 DNA Sequence (SEQ ID NO: 74) andProtein Sequence (SEQ ID NO: 75) of S1.1atg ttc act gtg ttt ctg ttg gtt gtc ttg gca atcMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Ileact gtc gtt tcc ttc cct tta gat cgt gaa tct gatThr Val Val Ser Phe Pro Leu Asp Arg Glu Ser Aspggc gcg aat gcc gaa gcc cgc acc cac gat cat gagGly Ala Asn Ala Glu Ala Arg Thr His Asp His Gluaag cac gca ctg gac cgg aat gga tgc tgt agg aatLys His Ala Leu Asp Arg Asn Gly Cys Cys Arg Asncct gcc tgt gag agc cac aga tgt ggt tgacgacgctPro Ala Cys Glu Ser His Arg Cys Glygatgctccag gaccctctga accacgacgt tcgagca

TABLE 10  DNA Sequence (SEQ ID NO: 76) andProtein Sequence (SEQ ID NO: 77) of Bn1.1atg ttc acc atg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Met Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc ttc gct tca gat cgt gca tct gatThr Val Val Ser Phe Ala Ser Asp Arg Ala Ser Aspggc agg aat gcc gca gcc aag gac aaa gcg tct gacGly Arg Asn Ala Ala Ala Lys Asp Lys Ala Ser Aspctg gtc gct ctg acc gtc aag gga tgc tgt tct catLeu Val Ala Leu Thr Val Lys Gly Cys Cys Ser Hiscct gcc tgt agc gtg aat aat cca gac att tgt ggtPro Ala Cys Ser Val Asn Asn Pro Asp Ile Cys Glytgaagacgct gatgctccag gaccctctga accacgacgt tcgagca

TABLE 11 DNA Sequence (SEQ ID NO: 78) andProtein Sequence (SEQ ID NO: 79) of Bn1.2aaa gaa tgc tgt act cat cct gcc tgt cac gtg agtLys Glu Cys Cys Thr His Pro Ala Cys His Val Sercat cca gaa ctc tgt ggt tgaaaagcga cgtgacgctc His Pro Glu Leu Cys Glycaggaccctc tgaaccacga cgttcgagca

TABLE 12 DNA Sequence (SEQ ID NO: 80) andProtein Sequence (SEQ ID NO: 81) of Bn1.3atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca actMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thrgct gtt ctt cca gtc act tta gat cgt gca tct gatAla Val Leu Pro Val Thr Leu Asp Arg Ala Ser Aspgga agg aat gca gca gcc aac gcc aaa acg cct cgcGly Arg Asn Ala Ala Ala Asn Ala Lys Thr Pro Argctg atc gcg cca ttc atc agg gat tat tgc tgt catLeu Ile Ala Pro Phe Ile Arg Asp Tyr Cys Cys Hisaga ggt ccc tgt atg gta tgg tgt ggt tgaagccgctArg Gly Pro Cys Met Val Trp Cys Gly gctgctccag gaccctctga accac

TABLE 13 DNA Sequence (SEQ ID NO: 82) andProtein Sequence (SEQ ID NO: 83) of Ca1.1atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtg gtt tcc ttc act tca gat cgt gct tct gatThr Val Val Ser Phe Thr Ser Asp Arg Ala Ser Aspggc agg aat gcc gca gcc aac gcg ttt gac ctg atcGly Arg Asn Ala Ala Ala Asn Ala Phe Asp Leu Ileget ctg atc gcc agg caa aat tgc tgt agc att cccAla Leu Ile Ala Arg Gln Asn Cys Cys Ser Ile Proagc tgt tgg gag aaa tat aaa tgt agt taaSer Cys Trp Glu Lys Tyr Lys Cys Ser

TABLE 14 DNA Sequence (SEQ ID NO: 84) andProtein Sequence (SEQ ID NO: 85) of Ca1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtg gtt tcc ttc act tca gat cgt gcg tct gaaThr Val Val Ser Phe Thr Ser Asp Arg Ala Ser Gluggc agg aat get gca gcc aag gac aaa gcg tct gacGly Arg Asn Ala Ala Ala Lys Asp Lys Ala Ser Aspctg gtg get ctg aca gtc agg gga tgc tgt gcc attLeu Val Ala Leu Thr Val Arg Gly Cys Cys Ala Ilecgt gaa tgt cgc ttg cag aat gca gcg tat tgt ggtArg Glu Cys Arg Leu Gln Asn Ala Ala Tyr Cys Gly gga ata tac tgatgctcca ggaccctctg aaccacgacg Gly Ile Tyr

TABLE 15 DNA Sequence (SEQ ID NO: 86) andProtein Sequence (SEQ ID NO: 87) of TIBatg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc ttc cct tca gat att gca act gagThr Val Val Ser Phe Pro Ser Asp Ile Ala Thr Gluggc agg aat gcc gca gcc aaa gcg ttt gac ctg ataGly Arg Asn Ala Ala Ala Lys Ala Phe Asp Leu Iletct tcg atc gtc aag aaa gga tgc tgt tcc cat cctSer Ser Ile Val Lys Lys Gly Cys Cys Ser His Progcc tgt tcg ggg aat aat cca gaa ttt tgt cgt caaAla Cys Ser Gly Asn Asn Pro Glu Phe Cys Arg Glnggt cgc tgatgctcca ggaccctctg aaccacgacg t Gly Arg

TABLE 16 DNA Sequence (SEQ ID NO: 88) andProtein Sequence (SEQ ID NO: 89) of TIAatg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc ttc cct tca gat ata gca act gagThr Val Val Ser Phe Pro Ser Asp Ile Ala Thr Gluggc agg aat gcc gca gcc aaa gcg ttt gac ctg ataGly Arg Asn Ala Ala Ala Lys Ala Phe Asp Leu Iletct tcg atc gtc agg aaa gga tgc tgt tcc aat cccSer Ser Ile Val Arg Lys Gly Cys Cys Ser Asn Progcc tgt gcg ggg aat aat cca cat gtt tgt cgt caaAla Cys Ala Gly Asn Asn Pro His Val Cys Arg Glnggt cgc tgatgctcca ggaccctctg aaccacgacg t Gly Arg

TABLE 17 DNA Sequence (SEQ ID NO: 90) andProtein Sequence (SEQ ID NO: 91) of Sl1.1atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ttc aat tca gat cgt gat cca gcaThr Val Val Ser Phe Asn Ser Asp Arg Asp Pro Alatta ggt ggc agg aat gct gca gcc aaa gcg tct gacLeu Gly Gly Arg Asn Ala Ala Ala Lys Ala Ser Aspaag atc get tcg acc ctc aag aga aga gga tgc tgtLys Ile Ala Ser Thr Leu Lys Arg Arg Gly Cys Cystcg tat ttt gac tgt aga atg atg ttt cca gaa atgSer Tyr Phe Asp Cys Arg Met Met Phe Pro Glu Mettgt ggt tgg cga ggc tgatgctcca ggaccctctg Cys Gly Trp Arg Glyaaccacgacg t

TABLE 18 DNA Sequence (SEQ ID NO: 92) andProtein Sequence (SEQ ID NO: 93) of Sl1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ttc aat tca gat cgt gat cca gcaThr Val Val Ser Phe Asn Ser Asp Arg Asp Pro Alatta ggt ggc agg aat get gca gcc ata gcg tct gacLeu Gly Gly Arg Asn Ala Ala Ala Ile Ala Ser Aspaag atc gct tcg acc ctc agg aga gga gga tgc tgtLys Ile Ala Ser Thr Leu Arg Arg Gly Gly Cys Cystct ttt cct gcc tgt aga aag tat cgt cca gaa atgSer Phe Pro Ala Cys Arg Lys Tyr Arg Pro Glu Mettgt ggt gga cgacgc tgatgctcca ggaccctctg Cys Gly Gly Arg Argaaccacgacg t

TABLE 19 DNA Sequence (SEQ ID NO: 94) andProtein Sequence (SEQ ID NO: 95) of Sl1.3atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ttc act tca gat cat gaa tct gatThr Val Val Ser Phe Thr Ser Asp His Glu Ser Aspcgc ggt gat gcc caa acc atc caa gaa gtg ttt gagArg Gly Asp Ala Gln Thr Ile Gln Glu Val Phe Gluatg ttc gct ctg gac agc gat gga tgc tgt tgg catMet Phe Ala Leu Asp Ser Asp Gly Cys Cys Trp Hiscct gct tgt ggc aga cac tat tgt ggt cga aga cgcPro Ala Cys Gly Arg His Tyr Cys Gly Arg Arg Argtgatgctcca ggaccctctg aaccacgacg t

TABLE 20 DNA Sequence (SEQ ID NO: 96) and Protein Sequence (SEQ ID NO: 97) of Sl1.6atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ttc aat tca gat cgt gat cca gcaThr Val Val Ser Phe Asn Ser Asp Arg Asp Pro Alatta ggt ggc agg aat gct gca gcc ata gcg tct gacLeu Gly Gly Arg Asn Ala Ala Ala Ile Ala Ser Aspaag atc gct tcg acc ctc agg aga gga gga tgc tgtLys Ile Ala Ser Thr Leu Arg Arg Gly Gly Cys Cystct ttt gct gcc tgt aga aag tat cgt cca gaa atgSer Phe Ala Ala Cys Arg Lys Tyr Arg Pro Glu Mettgt ggt gga cga cgc tgatgct Cys Gly Gly Arg Arg

TABLE 21 DNA Sequence (SEQ ID NO: 98) and Protein Sequence (SEQ ID NO: 99) of Sl1.7atg ttc acc gtg ttt ctg ttg gtt ctc ttg gca accMet Phe Thr Val Phe Leu Leu Val Leu Leu Ala Thracc gtc gtt tcc ttc aat tca gat cgt gca tta ggtThr Val Val Ser Phe Asn Ser Asp Arg Ala Leu Glyggc agg aat gct gca gcc aaa gcg tct gac aag atcGly Arg Asn Ala Ala Ala Lys Ala Ser Asp Lys Ilectt tcg aac ctc agg aga gga gga tgc tgt ttt catLeu Ser Asn Leu Arg Arg Gly Gly Cys Cys Phe Hiscct gtc tgt tac atc aat ctt cta gaa atg tgt cgtPro Val Cys Tyr Ile Asn Leu Leu Glu Met Cys Argcaa cga ggc tgatcgtcca ggaccctctg aaccacgacg t Gln Arg Gly

TABLE 22 DNA Sequence (SEQ ID NO: 100) and Protein Sequence (SEQ ID NO: 101) of Cn1.1atg ttc acc gtg ttt ctg ttg gtt gtc ttg aca accMet Phe Thr Val Phe Leu Leu Val Val Leu Thr Thract gtc gtt tcc ttc cct tca gat agt gca tct gatThr Val Val Ser Phe Pro Ser Asp Ser Ala Ser Aspgtc agg gat gac gaa gcc aaa gac gaa agg tct gacVal Arg Asp Asp Glu Ala Lys Asp Glu Arg Ser Aspatg tac aaa tcg aaa cgg aat gga cgc tgt tgc catMet Tyr Lys Ser Lys Arg Asn Gly Arg Cys Cys Hiscct gcc tgt ggc aaa cac ttt agt tgt gga cgc Pro Ala Cys Gly Lys His Phe Ser Cys Gly Argtgatgctcca ggaccctctg aaccacgacg t

TABLE 23 DNA Sequence(SEQ ID NO: 102)and Protein Sequence (SEQ ID NO: 103) of SmIatg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc tcc cct tca gat cgt gca tct gatThr Val Val Ser Ser Pro Ser Asp Arg Ala Ser Aspggc agg aat gcc gca gcc aac gag aaa gcg tct gacGly Arg Asn Ala Ala Ala Asn Glu Lys Ala Ser Aspgtg atc gcg ctg gcc ctc aag gga tgc tgt tcc aacVal Ile Ala Leu Ala Leu Lys Gly Cys Cys Ser Asncct gtc tgt cac ctg gag cat tca aac atg tgt ggtPro Val Cys His Leu Glu His Ser Asn Met Cys Glyaga aga cgc tgatgctcca ggaccctctg aaccacgacg Arg Arg Arg

TABLE 24 DNA Sequence (SEQ ID NO: 104) and Protein Sequence (SEQ ID NO: 105) of Bt1.1atg ttc tcc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Ser Val Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc tcc act tca ggt ggt gca tct ggtThr Val Val Ser Ser Thr Ser Gly Gly Ala Ser Glyggc agg aag gct gca gcc aaa gcg tct aac cgg atcGly Arg Lys Ala Ala Ala Lys Ala Ser Asn Arg Ilegct ctg acc gtc agg agt gca aca tgc tgt aat tatAla Leu Thr Val Arg Ser Ala Thr Cys Cys Asn Tyrcct ccc tgt tac gag act tat cca gaa agt tgt ctgPro Pro Cys Tyr Glu Thr Tyr Pro Glu Ser Cys Leutaacgtgaat catccagagc tttgtggctg aagacactgatgctccagga ccctctgaac cacgacgt

TABLE 25 DNA Sequence (SEQ ID NO: 106) and Protein Sequence (SEQ ID NO: 107) of Bt1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtg gtt tcc ttc act tca ggt cgt gca ttt cgtThr Val Val Ser Phe Thr Ser Gly Arg Ala Phe Argggc agg aat cgc gca gcc gac gac aaa agg tct gacGly Arg Asn Arg Ala Ala Asp Asp Lys Arg Ser Aspctg gcc gct ctg agc gtc agg gga gga tgc tgt tccLeu Ala Ala Leu Ser Val Arg Gly Gly Cys Cys Sercat cct gcc tgt gcg gtg aat cat cca gag ctt tgtHis Pro Ala Cys Ala Val Asn His Pro Glu Leu Cysggc tgaagacgct gatgccccag gaccctctga accacgacgt Gly

TABLE 26 DNA Sequence (SEQ ID NO: 108) and Protein Sequence (SEQ ID NO: 109) of Bt1.3atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc ttc act tca ggt cgt gca tct ggtThr Val Val Ser Phe Thr Ser Gly Arg Ala Ser Glyggc agg aat gct gca gcc aaa gcg tct aac cgg atcGly Arg Asn Ala Ala Ala Lys Ala Ser Asn Arg Ilegct atg gcc atc agc agt gga gca tgc tgt gca tatAla Met Ala Ile Ser Ser Gly Ala Cys Cys Ala Tyrcct ccc tgt ttc gag gct tat cca gaa aga tgt ctgPro Pro Cys Phe Glu Ala Tyr Pro Glu Arg Cys Leutaacgtgaat catccagacc tttgtggctg aagacgctgatgccccagga ccctctgaac cacgacgt

TABLE 27 DNA Sequence (SEQ ID NO: 110) and Protein Sequence (SEQ ID NO: 111) of Bt1.4atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc ttc act tca gat cgt gca ttt cgtThr Val Val Ser Phe Thr Ser Asp Arg Ala Phe Argggc agg aat tcc gca gcc aac gac aaa agg tct gacGly Arg Asn Ser Ala Ala Asn Asp Lys Arg Ser Aspctg gcc gct ctg agc gtc agg aga gga tgc tgc tccLeu Ala Ala Leu Ser Val Arg Arg Gly Cys Cys Sercat ccc gcc tgt agc gtg aat cat cca gag ctt tgtHis Pro Ala Cys Ser Val Asn His Pro Glu Leu Cysggt aga aga cgc tgatgcccca ggaccctctg aaccacgacg Gly Arg Arg Arg t

TABLE 28 DNA Sequence (SEQ ID NO: 112) and Protein Sequence (SEQ ID NO: 113) of Bt1.5atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc ttc act tca ggt cgt gca tct ggtThr Val Val Ser Phe Thr Ser Gly Arg Ala Ser Glyggc agg aat gct gca gcc aaa gcg tct aac cgg atcGly Arg Asn Ala Ala Ala Lys Ala Ser Asn Arg Ilegct ctg atc gtc agg aat gca gaa tgc tgt tat tatAla Leu Ile Val Arg Asn Ala Glu Cys Cys Tyr Tyrcct ccc tgt tac gag gct tat cca gaa att tgt ctgPro Pro Cys Tyr Glu Ala Tyr Pro Glu Ile Cys Leutaacgtgaat catccagacc tttgtggctg aagaccctgatgctccagga ccctctgaac cacgacgt

TABLE 29 DNA Sequence (SEQ ID NO: 114) and Protein Sequence (SEQ ID NO: 115) of Pn1.1atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc att tcc ttc act tca gat cgt gca tct gatThr Val Ile Ser Phe Thr Ser Asp Arg Ala Ser Aspggc ggg aat gcc gca gcg tct gac ctg atc gct ctgGly Gly Asn Ala Ala Ala Ser Asp Leu Ile Ala Leuacc atc aag gga tgc tgt tct cat cct ccc tgt gccThr Ile Lys Gly Cys Cys Ser His Pro Pro Cys Alaatg aat aat cca gac tat tgt ggt tgacgacgctMet Asn Asn Pro Asp Tyr Cys Gly gatgctccag gaccctctga accacgacg

TABLE 30 DNA Sequence (SEQ ID NO: 116) and Protein Sequence (SEQ ID NO: 117) of Pn1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ttc act tca gat cgt gca tct gatThr Val Val Ser Phe Thr Ser Asp Arg Ala Ser Aspggc ggg aat gcc gca atg tct gac ctg atc gct ctgGly Gly Asn Ala Ala Met Ser Asp Leu Ile Ala Leuacc atc aag gga tgc tgt tct cat cct ccc tgt ttcThr Ile Lys Gly Cys Cys Ser His Pro Pro Cys Phectg aat aat cca gac tat tgt ggt tgacgacgctLeu Asn Asn Pro Asp Tyr Cys Gly gatgctccag gaccctctga accacgacg

TABLE 31 DNA Sequence (SEQ ID NO: 118) and Protein Sequence (SEQ ID NO: 119) of Sm1.3atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc ttc cct tca gat cgt gaa tct gatThr Val Val Ser Phe Pro Ser Asp Arg Glu Ser Aspggc gcg aat gac gaa gcc cgc acc gac gag cct gagGly Ala Asn Asp Glu Ala Arg Thr Asp Glu Pro Glugag cac gga ccg gac agg aat gga tgc tgt agg aatGlu His Gly Pro Asp Arg Asn Gly Cys Cys Arg Asncct gcc tgt gag agc cac aga tgt ggt tgacgacgctPro Ala Cys Glu Ser His Arg Cys Gly gatgctccag gaccctctga accacgacg

TABLE 32 DNA Sequence (SEQ ID NO: 120) and Protein Sequence (SEQ ID NO: 121) of Cr1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc ttc cct tca gat cgt gca tct gatThr Val Val Ser Phe Pro Ser Asp Arg Ala Ser Aspggc agg aat gcc gca gcc agc gac aga gcg tct gacGly Arg Asn Ala Ala Ala Ser Asp Arg Ala Ser Aspgcg gcc cac cag gga tgc tgt tcc aac cct gtc tgtAla Ala His Gln Gly Cys Cys Ser Asn Pro Val Cyscac gtg gaa cat cca gaa ctt tgt cgt aga aga cgcHis Val Glu His Pro Glu Leu Cys Arg Arg Arg Argtgatgctcca ggaccctctg aaccacgacg

TABLE 33 DNA Sequence (SEQ ID NO: 122) and Protein Sequence (SEQ ID NO: 123) of Cr1.3atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc ttc cct tca aat cgt gaa tct gatThr Val Val Ser Phe Pro Ser Asn Arg Glu Ser Aspggc gcg aat gcc gaa gtc cgc acc gac gag cct gagGly Ala Asn Ala Glu Val Arg Thr Asp Glu Pro Glugag cac gac gaa ctg ggc ggg aat gga tgc tgt gggGlu His Asp Glu Leu Gly Gly Asn Gly Cys Cys Glyaat cct gac tgt acg agc cac agt tgt gatAsn Pro Asp Cys Thr Ser His Ser Cys Asptgacgacgct gatgctccag gaccctctga accacgacg

TABLE 34 DNA Sequence (SEQ ID NO: 124) andProtein Sequence (SEQ ID NO: 125) of EpIatg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tccMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Serttc act tca gat cgt gca tct gat agc agg aag gac gca gcg tct ggcPhe Thr Ser Asp Arg Ala Ser Asp Ser Arg Lys Asp Ala Ala Ser Glyctg atc gct ctg acc atc aag gga tgc tgt tct gat cct cgc tgt aacLeu Ile Ala Leu Thr Ile Lys Gly Cys Cys Ser Asp Pro Arg Cys Asnatg aat aat cca gac tat tgt ggt tgacgacgct gatgctccag gaccctctgaMet Asn Asn Pro Asp Tyr Cys Gly accacgacg

TABLE 35 DNA Sequence (SEQ ID NO: 126) andProtein Sequence (SEQ ID NO: 127) of Sn1.1atg tcc acc gtg ttt ctg ttg gtt gtc ctc gca acc acc gtc gtt tccMet Ser Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Serttc act gta gat cgt gca tct gat ggc agg gat gtc gca atc gac gacPhe Thr Val Asp Arg Ala Ser Asp Gly Arg Asp Val Ala Ile Asp Aspaga ttg gtg tct ctc cct cag atc gcc cat gct gac tgt tgt tcc gatArg Leu Val Ser Leu Pro Gln Ile Ala His Ala Asp Cys Cys Ser Aspcct gcc tgc aag cag acg ccc ggt tgt cgt taaagacgct gctgctccagPro Ala Cys Lys Gln Thr Pro Gly Cys Arg gaccctctga accacgacg

TABLE 36 DNA Sequence (SEQ ID NO: 128) andProtein Sequence (SEQ ID NO: 129) of Sn1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gct tccMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Ala Serttc att atc gat gat cca tct gat ggc agg aat att gca gtc gac gacPhe Ile Ile Asp Asp Pro Ser Asp Gly Arg Asn Ile Ala Val Asp Aspaga ggg ctt ttc tct acg ctc ttc cat gct gat tgc tgt gaa aat cctArg Gly Leu Phe Ser Thr Leu Phe His Ala Asp Cys Cys Glu Asn Progcc tgt aga cac acg cag ggt tgt tgatctttgt tcttcaaaga cactgctggcAla Cys Arg His Thr Gln Gly Cys ccaggaccct ctgaaccacg acg

TABLE 37 DNA Sequence (SEQ ID NO: 130) andProtein Sequence (SEQ ID NO: 131) of Da1.1atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tccMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Serttc act tca gat cgt gca ttt cgt ggc agg aat gcc gca gcc aaa gagPhe Thr Ser Asp Arg Ala Phe Arg Gly Arg Asn Ala Ala Ala Lys Glutct ggc ctg gtc ggt ctg acc gac aag acg cga gga tgc tgt tct catSer Gly Leu Val Gly Leu Thr Asp Lys Thr Arg Gly Cys Cys Ser Hiscct gcc tgt aac gta gat cat cca gaa att tgt ggt tgaagacgctPro Ala Cys Asn Val Asp His Pro Glu Ile Cys Glygatgctccag gaccctctga accacgacgt

TABLE 38 DNA Sequence (SEQ ID NO: 132) andProtein Sequence (SEQ ID NO: 133) of Da1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tccMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Serttc act tca gat ggt gca tct gat gac agg aaa gcc gct gcg tct gacPhe Thr Ser Asp Gly Ala Ser Asp Asp Arg Lys Ala Ala Ala Ser Aspctg atc act ctg acc atc aag gga tgc tgt tct cgt cct ccc tgt atcLeu Ile Thr Leu Thr Ile Lys Gly Cys Cys Ser Arg Pro Pro Cys Ilegcg aat aat cca gac ttg tgt ggt cga cga cgc tgatgctcca ggaccctctgAla Asn Asn Pro Asp Leu Cys Gly Arg Arg Arg

TABLE 39 DNA Sequence (SEQ ID NO: 134) andProtein Sequence (SEQ ID NO: 135) of Da1.3atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tccMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Sertcc act tca ggt cgt cgt gca ttt cat ggc agg aat gcc gca gcc aaaSer Thr Ser Gly Arg Arg Ala Phe His Gly Arg Asn Ala Ala Ala Lysgcg tct gga ctg gtc ggt ctg act gac agg aga cca caa tgc tgt agtAla Ser Gly Leu Val Gly Leu Thr Asp Arg Arg Pro Gln Cys Cys Sergat cct cgc tgt aac gta ggt cat cca gaa ctt tgt ggt gga aga cgcAsp Pro Arg Cys Asn Val Gly His Pro Glu Leu Cys Gly Gly Arg Argtgatgctcca ggaccctctg aaccacaacg t

TABLE 40 DNA Sequence (SEQ ID NO: 136) and Protein Sequence (SEQ ID NO: 137) of Da1.4atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tccMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Sertcc act tca ggt cgt gca ttt cat ggc agg aat gcc gca gcc aaa gcgSer Thr Ser Gly Arg Ala Phe His Gly Arg Asn Ala Ala Ala Lys Alatct ggc ctg gtc ggt ctg acc gac aag agg caa gta tgc tgt agt gatSer Gly Leu Val Gly Leu Thr Asp Lys Arg Gln Val Cys Cys Ser Aspcct cgc tgt aac gta ggt cat cca gaa att tgt ggt gga aga cgcPro Arg Cys Asn Val Gly His Pro Glu Ile Cys Gly Gly Arg Argtgatgctcca ggaccctctg aaccacgacg t

TABLE 41 DNA Sequence (SEQ ID NO: 138) andProtein Sequence (SEQ ID NO: 139)of A1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg aca acc act gtc gtt tccMet Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr Thr Val Val Serttc cct tca gat agt gca tct ggt ggc agg gat gac gag gcc aaa gacPhe Pro Ser Asp Ser Ala Ser Gly Gly Arg Asp Asp Glu Ala Lys Aspgaa agg tct gac atg tac gaa ttg aaa cgg aat gga cgc tgt tgc catGlu Arg Ser Asp Met Tyr Glu Leu Lys Arg Asn Gly Arg Cys Cys Hiscct gcc tgt ggt ggc aaa tac gtt aaa tgt gga cgc tgatgctccaPro Ala Cys Gly Gly Lys Tyr Val Lys Cys Gly Arg ggaccctctc gaaccacg

TABLE 42 DNA Sequence (SEQ ID NO: 140) andProtein Sequence (SEQ ID NO: 141) of Bu1.1atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tccMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Serttc tct aca gat gat gaa tct gat ggc tcg aat gaa gaa ccc agc gccPhe Ser Thr Asp Asp Glu Ser Asp Gly Ser Asn Glu Glu Pro Ser Alagac cag act gcc agg tcc tca atg aac agg gcg cct gga tgc tgt aacAsp Gln Thr Ala Arg Ser Ser Met Asn Arg Ala Pro Gly Cys Cys Asnaat cct gcc tgt gtg aag cac aga tgt gga tgacgctgat gctccaggacAsn Pro Ala Cys Val Lys His Arg Cys Gly cctctgaacc acgacgt

TABLE 43 DNA Sequence (SEQ ID NO: 142) andProtein Sequence (SEQ ID NO: 143) of Bu1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tccMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Serttc tct aca gat gat gaa tct gat ggc tcg aat gaa gaa ccc agc gccPhe Ser Thr Asp Asp Glu Ser Asp Gly Ser Asn Glu Glu Pro Ser Alagac cag gct gcc agg tcc gca atg aac agg ccg cct gga tgc tgt aacAsp Gln Ala Ala Arg Ser Ala Met Asn Arg Pro Pro Gly Cys Cys Asnaat cct gcc tgt gtg aag cac aga tgt ggt gga tgacgctgat gctccaggacAsn Pro Ala Cys Val Lys His Arg Cys Gly Gly cctctgaacc acgacgt

TABLE 44 DNA Sequence (SEQ ID NO: 144) andProtein Sequence (SEQ ID NO: 145) of Bu1.3atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tccMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Serttc cct tca gat cgt gac tct gat ggc gcg gat gcc gaa gcc agt gacPhe Pro Ser Asp Arg Asp Ser Asp Gly Ala Asp Ala Glu Ala Ser Aspgag cct gtt gag ttc gaa agg gac gag aat gga tgc tgt tgg aat cctGlu Pro Val Glu Phe Glu Arg Asp Glu Asn Gly Cys Cys Trp Asn Protcc tgt ccg agg ccc aga tgt aca gga cga cgc taatgctcca ggaccctctgSer Cys Pro Arg Pro Arg Cys Thr Gly Arg Arg aaccacgacg t

TABLE 45 DNA Sequence (SEQ ID NO: 146) andProtein Sequence (SEQ ID NO: 170) of Bu1.4atg ttc acc gtg ttt ctg ttg gtt gtc ttg aca acc act gtc gtt tccMet Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr Thr Val Val Serttc cct tca gat cgt gca tct gat ggc agg aat gcc gca gcc aac gacPhe Pro Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Asn Aspaaa gcg tct gac gtg gtc acg ctg gtc ctc aag gga tgc tgt tcc accLys Ala Ser Asp Val Val Thr Leu Val Leu Lys Gly Cys Cys Ser Thrcct ccc tgt gct gtg ctg tat tgt ggt aga aga cgc tgatgctccaPro Pro Cys Ala Val Leu Tyr Cys Gly Arg Arg Arg ggaccctctg aaccacgacg t

TABLE 46 DNA Sequence (SEQ ID NO: 148) andProtein Sequence (SEQ ID NO: 149) of Di1.1atg ttc acc gtg ttt ctg ttg gtt gtc ttc gca tcc tct gtc acc ttaMet Phe Thr Val Phe Leu Leu Val Val Phe Ala Ser Ser Val Thr Leugat cgt gca tct tat ggc agg tat gcc tca ccc gtc gac aga gcg tctAsp Arg Ala Ser Tyr Gly Arg Tyr Ala Ser Pro Val Asp Arg Ala Sergcc ctg atc gct cag gcc atc ctt cga gat tgc tgc tcc aat cct cctAla Leu Ile Ala Gln Ala Ile Leu Arg Asp Cys Cys Ser Asn Pro Protgt gcc cat aat aat cca gac tgt cgt taaagacgct gcttgctccaCys Ala His Asn Asn Pro Asp Cys Arg ggaccctct gaaccacgacg t

TABLE 47 DNA Sequence (SEQ ID NO: 150) andProtein Sequence (SEQ ID NO: 151) of T1gga tgc tgt tct aat cct ccc tgt atc gcg aag aat cca cac atg tgtGly Cys Cys Ser Asn Pro Pro Cys Ile Ala Lys Asn Pro His Met Cysggt gga aga cgc tga Gly Gly Arg Arg

TABLE 48 DNA Sequence (SEQ ID NO: 152) andProtein Sequence (SEQ ID NO: 153) of Cn1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tccMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Serttc cct tca gat cgt gca tct gat ggc agg aat gcc gca gcc aac gacPhe Pro Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Asn Aspaaa gcg tct gac gtg atc acg ctg gcc ctc aag gga tgc tgt tcc aacLys Ala Ser Asp Val Ile Thr Leu Ala Leu Lys Gly Cys Cys Ser Asncct gtc tgt cac ttg gag cat tca aac ctt tgt ggt aga aga cgcPro Val Cys His Leu Glu His Ser Asn Leu Cys Gly Arg Arg Argtgatgctcca ggaccctctg aaccacgacg t

TABLE 49 DNA Sequence (SEQ ID NO: 233) and ProteinSequence (SEQ ID NO: 234) of Im1.1tct gat gga aag agt gcc gcg gcc aaa gcc aaa ccgSer Asp Gly Lys Ser Ala Ala Ala Lys Ala Lys Protct cac ctg acg gct cca ttc atc agg gac gaa tgcSer His Leu Thr Ala Pro Phe Ile Arg Asp Glu Cystgt tcc gat tct cgc tgt ggc aag aac tgt ctt tgaCys Ser Asp Ser Arg Cys Gly Lys Asn Cys Leu

TABLE 50 DNA Sequence (SEQ ID NO: 235) and ProteinSequence (SEQ ID NO: 236) of Im1.2ttt gat gga agg aat gcc cca gcc gac gac aaa gcgPhe Asp Gly Arg Asn Ala Pro Ala Asp Asp Lys Alatct gac ctg atc gct caa atc gtc agg aga gca tgcSer Asp Leu Ile Ala Gln Ile Val Arg Arg Ala Cystgt tcc gat cgt cgc tgt aga tgg agg tgt ggt tgaCys Ser Asp Arg Arg Cys Arg Trp Arg Cys Gly

TABLE 51 DNA Sequence (SEQ ID NO: 237) and ProteinSequence (SEQ ID NO: 238) of Rg1.2tct gat gga agg aat gcc gca gcc gac gcc aga gcgSer Asp Gly Arg Asn Ala Ala Ala Asp Ala Arg Alatct ccc cgg atc gct ctt ttc ctc agg ttc aca tgcSer Pro Arg Ile Ala Leu Phe Leu Arg Phe Thr Cystgt agg aga ggt acc tgt tcc cag cac tgt ggtCys Arg Arg Gly Thr Cys Ser Gln His Cys Glytgaagacact gctgctccag gaccctctga accacgacgt

TABLE 52 DNA Sequence (SEQ ID NO: 239) and ProteinSequence (SEQ ID NO: 240) of Rg1.6tct aat gga agg aat gcc gca gcc gac gcc aaa gcgSer Asn Gly Arg Asn Ala Ala Ala Asp Ala Lys Alatct caa cgg atc gct cca ttc ctc agg gac tat tgcSer Gln Arg Ile Ala Pro Phe Leu Arg Asp Tyr Cystgt agg aga cat gcc tgt acg ttg att tgt ggtCys Arg Arg His Ala Cys Thr Leu Ile Cys Glytgaagacgct gctgctccag gaccctctga accacgacgt

TABLE 53 DNA Sequence (SEQ ID NO: 241) and ProteinSequence (SEQ ID NO: 242) of Rg1.6Atct aat gga agg aat gcc gca gcc gac gcc aaa gcgSer Asn Gly Arg Asn Ala Ala Ala Asp Ala Lys Alatct caa cgg atc gct cca ttc ctc agg gac tat tgcSer Gln Arg Ile Ala Pro Phe Leu Arg Asp Tyr Cystgt agg aga cct ccc tgt acg ttg att tgt ggtCys Arg Arg Pro Pro Cys Thr Leu Ile Cys Glytgaagacgct gctgctccag gaccctctga accacgacgt

TABLE 54 DNA Sequence (SEQ ID NO: 243) and ProteinSequence (SEQ ID NO: 244) of Rg1.7tct aat aaa agg aag aat gcc gca atg ctt gac atgSer Asn Lys Arg Lys Asn Ala Ala Met Leu Asp Metatc gct caa cac gcc ata agg ggt tgc tgt tcc gatIle Ala Gln His Ala Ile Arg Gly Cys Cys Ser Aspcct cgc tgt aga tat aga tgt cgt tgaagacgctPro Arg Cys Arg Tyr Arg Cys Arg gctgctccag gaccctctga accacgacgt

TABLE 55 DNA Sequence (SEQ ID NO: 245) and ProteinSequence (SEQ ID NO: 246) of Rg1.9ttt aat gga agg agt gcc gca gcc gac caa aat gcgPhe Asn Gly Arg Ser Ala Ala Ala Asp Gln Asn Alacct ggc ctg atc gct caa gtc gtc aga gga ggg tgcPro Gly Leu Ile Ala Gln Val Val Arg Gly Gly Cystgt tcc gat ccc cgc tgc gcc tgg aga tgt ggtCys Ser Asp Pro Arg Cys Ala Trp Arg Cys Glytgaagacgtt gctgctccag gaccctctga accacgacgt

TABLE 56 DNA Sequence (SEQ ID NO: 247) and ProteinSequence (SEQ ID NO: 248) of Rg1.10ttt gat gga agg aat gcc gca gcc gac gcc aaa gtgPhe Asp Gly Arg Asn Ala Ala Ala Asp Ala Lys Valatt aac acg gtc gct cga atc gcc tgg gat ata tgcIle Asn Thr Val Ala Arg Ile Ala Trp Asp Ile Cystgt tcc gaa cct gac tgt aac cat aaa tgt gttCys Ser Glu Pro Asp Cys Asn His Lys Cys Valtgaagacgct tctgctccag gaccctctga accacgacgt

TABLE 57 DNA Sequence (SEQ ID NO: 249) and ProteinSequence (SEQ ID NO: 250) of Rg1.11tct aat aaa agg aag aat gcc gca atg ctt gac atgSer Asn Lys Arg Lys Asn Ala Ala Met Leu Asp Metatc gct caa cac gcc ata agg ggt tgc tgt tcc gatIle Ala Gln His Ala Ile Arg Gly Cys Cys Ser Aspcct cgc tgt aaa cat cag tgt ggt tgaagacgctPro Arg Cys Lys His Gln Cys Gly gctgctccag gaccctctga accacgacgt

TABLE 58 DNA Sequence (SEQ ID NO: 251) and ProteinSequence (SEQ ID NO: 252) of Ms1.7atc aag aat aca gca gcc agc aac aaa gcg tct agcIle Lys Asn Thr Ala Ala Ser Asn Lys Ala Ser Serctg gtg gct ctt gtt gtc agg gga tgc tgt tac aatLeu Val Ala Leu Val Val Arg Gly Cys Cys Tyr Asncct gtc tgc aag aaa tat tat tgt tgg aaa ggcPro Val Cys Lys Lys Tyr Tyr Cys Trp Lys Glytgatgctcca ggaccctctg aaccacgacg t

TABLE 59 DNA Sequence (SEQ ID NO: 253) and ProteinSequence (SEQ ID NO: 254) of P1.7tct gaa ggc agg aat gct gaa gcc atc gac aac gccSer Glu Gly Arg Asn Ala Glu Ala Ile Asp Asn Alatta gac cag agg gat cca aag cga cag gag ccg gggLeu Asp Gln Arg Asp Pro Lys Arg Gln Glu Pro Glytgc tgt agg cat cct gcc tgt ggg aag aac aga tgtCys Cys Arg His Pro Ala Cys Gly Lys Asn Arg Cysgga aga cgc tgatgctccag gaccctctg aaccacgacg t Gly Arg Arg

TABLE 60 DNA Sequence (SEQ ID NO: 255) and ProteinSequence (SEQ ID NO: 256) of Ms1.2tct gat ggc agg aat att gca gtc gac gac aga tggSer Asp Gly Arg Asn Ile Ala Val Asp Asp Arg Trptct ttc tat acg ctc ttc cat gct act tgc tgt gccSer Phe Tyr Thr Leu Phe His Ala Thr Cys Cys Alagat cct gac tgt aga ttc cgg ccc ggt tgt Asp Pro Asp Cys Arg Phe Arg Pro Gly Cystgatctttgt tcttcaaaga cgctgctggc ccaggaccct ctgaaccacg acgt

TABLE 61 DNA Sequence (SEQ ID NO: 257) and ProteinSequence (SEQ ID NO: 258) of Ms1.3atc aag aat act gca gcc agc aac aaa gcg cct agcIle Lys Asn Thr Ala Ala Ser Asn Lys Ala Pro Serctg gtg gct att gcc gtc agg gga tgc tgt tac aatLeu Val Ala Ile Ala Val Arg Gly Cys Cys Tyr Asncct tcc tgt tgg ccg aaa aca tat tgt agtPro Ser Cys Trp Pro Lys Thr Tyr Cys Sertggaaaggct gatgctccag gaccctctga accacgacgt

TABLE 62 DNA Sequence (SEQ ID NO: 259) and ProteinSequence (SEQ ID NO: 260) of Ms1.4tct gat agc agg aat gtc gca atc gag gac aga gtgSer Asp Ser Arg Asn Val Ala Ile Glu Asp Arg Valtct gac ctg cac tct atg ttc ttc gat gtt tct tgcSer Asp Leu His Ser Met Phe Phe Asp Val Ser Cystgt agc aat cct acc tgt aaa gaa acg tat ggt tgtCys Ser Asn Pro Thr Cys Lys Glu Thr Tyr Gly Cystgatcgttgg ttttgaagac gctgatgctc caggaccctc

TABLE 63 DNA Sequence (SEQ ID NO: 261) and ProteinSequence (SEQ ID NO: 262) of Ms1.5tct gtt ggc agg aat att gca gtc gac gac aga gggSer Val Gly Arg Asn Ile Ala Val Asp Asp Arg Glyatt ttc tct acg ctc ttc cat gct cat tgc tgt gccIle Phe Ser Thr Leu Phe His Ala His Cys Cys Alaaat ccc atc tgt aaa aac acg ccc ggt tgtAsn Pro Ile Cys Lys Asn Thr Pro Gly Cystgatctttgt tcttcaaaga cgctgctggc ccaggaccct  ctgaaccacg acgt

TABLE 64 DNA Sequence (SEQ ID NO: 263) and ProteinSequence (SEQ ID NO: 264) of Ms1.8tcc gat ggc agg aat gtc gca atc gac gac aga gtgSer Asp Gly Arg Asn Val Ala Ile Asp Asp Arg Valtct gac ctg cac tct atg ttc ttc gat att gct tgcSer Asp Leu His Ser Met Phe Phe Asp Ile Ala Cystgt aac aat cct acc tgt aaa gaa acg tat ggt tgtCys Asn Asn Pro Thr Cys Lys Glu Thr Tyr Gly Cystgatcgttgg ttttgaagac gctgatgctc caggaccctc tgaaccacga cgt

TABLE 65 DNA Sequence (SEQ ID NO: 265) and ProteinSequence (SEQ ID NO: 266) of Ms1.9tct gat ggc agg aat gtc gca atc gag gac aga gtgSer Asp Gly Arg Asn Val Ala Ile Glu Asp Arg Valtct gac ctg ctc tct atg ctc ttc gat gtt gct tgcSer Asp Leu Leu Ser Met Leu Phe Asp Val Ala Cystgt agc aat cct gtc tgt aaa gaa acg tat ggt tgtCys Ser Asn Pro Val Cys Lys Glu Thr Tyr Gly Cystgatcgttgg ttttgaagac gctgatgctc caggaccctc tgaaccacga cgt

TABLE 66 DNA Sequence (SEQ ID NO: 267) and ProteinSequence (SEQ ID NO: 268) of Bt1.7tat gat ggc agg aat gct gcc gcc gac gac aaa gctTyr Asp Gly Arg Asn Ala Ala Ala Asp Asp Lys Alattt gac ctg ctg gct atg acc ata agg gga gga tgcPhe Asp Leu Leu Ala Met Thr Ile Arg Gly Gly Cystgt tcc tat cct ccc tgt atc gcg agt aat cct aaaCys Ser Tyr Pro Pro Cys Ile Ala Ser Asn Pro Lystgt ggt gga aga cgc tgatgctcca ggaccctctg Cys Gly Gly Arg Argaaccacaacg t

TABLE 67 DNA Sequence (SEQ ID NO: 269) and ProteinSequence (SEQ ID NO: 270) of Lv1.5ttt gat ggc agg aat gct gca ggc aac gcc aaa atgPhe Asp Gly Arg Asn Ala Ala Gly Asn Ala Lys Mettcc gcc ctg atg gcc ctg acc atc agg gga tgc tgtSer Ala Leu Met Ala Leu Thr Ile Arg Gly Cys Cystcc cat cct gtc tgt agc gcg atg agt cca atc tgtSer His Pro Val Cys Ser Ala Met Ser Pro Ile Cysggc tgaagacgct gatgccccag gaccctctga accacgacgt Gly

TABLE 68 DNA Sequence (SEQ ID NO: 271) and ProteinSequence (SEQ ID NO: 272) of Ms1.10atc aag aat gct gca gct gac gac aaa gca tct gacIle Lys Asn Ala Ala Ala Asp Asp Lys Ala Ser Aspctg ctc tct cag atc gtc agg aat gct gca tcc aatLeu Leu Ser Gln Ile Val Arg Asn Ala Ala Ser Asngac aaa ggg tct gac ctg atg act ctt gcc ctc aggAsp Lys Gly Ser Asp Leu Met Thr Leu Ala Leu Arggga tgc tgt aaa aat cct tac tgt ggt gcg tcg aaaGly Cys Cys Lys Asn Pro Tyr Cys Gly Ala Ser Lysaca tat tgt ggt aga aga cgc tgatgctcca ggaccctctgThr Tyr Cys Gly Arg Arg Arg aaccacgacg t

TABLE 69 DNA Sequence (SEQ ID NO: 273) and ProteinSequence (SEQ ID NO: 274) of Om1.1tctgatggca ggaatgccgc agcgtctgac ctgatggat ctg                                            Leuacc atc aag gga tgc tgt tct tat cct ccc tgt ttcThr Ile Lys Gly Cys Cys Ser Tyr Pro Pro Cys Phegcg act aat cca gac tgt ggt cga cga cgcAla Thr Asn Pro Asp Cys Gly Arg Arg Argtgatgctcca ggaccctctg aaccacgacg t

TABLE 70 DNA Sequence (SEQ ID NO: 275) and ProteinSequence (SEQ ID NO: 276) of R1.6ttt gat ggc agg aat gcc gca gcc gac tac aaa gggPhe Asp Gly Arg Asn Ala Ala Ala Asp Tyr Lys Glytct gaa ttg ctc gct atg acc gtc agg gga gga tgcSer Glu Leu Leu Ala Met Thr Val Arg Gly Gly Cystgt tcc tat cct ccc tgt atc gca aat aat cct cttCys Ser Tyr Pro Pro Cys Ile Ala Asn Asn Pro Leu tgt gct gga aga cgc tgaCys Ala Gly Arg Arg

TABLE 71 DNA Sequence (SEQ ID NO: 277) and ProteinSequence (SEQ ID NO: 278) of R1.7ttt gat ggc agg aat gcc gca gcc gac tac aaa gggPhe Asp Gly Arg Asn Ala Ala Ala Asp Tyr Lys Glytct gaa ttg ctc gct atg acc gtc agg gga gga tgcSer Glu Leu Leu Ala Met Thr Val Arg Gly Gly Cystgt tcc tat cct ccc tgt atc gca aat aat cct tttCys Ser Tyr Pro Pro Cys Ile Ala Asn Asn Pro Phe tgt gct gga aga cgc tgaCys Ala Gly Arg Arg

TABLE 72 DNA Sequence (SEQ ID NO: 279) and ProteinSequence (SEQ ID NO: 280) of Vr1.1tct tat gac agg tat gcc tcg ccc gtc gac aga gcgSer Tyr Asp Arg Tyr Ala Ser Pro Val Asp Arg Alatct gcc ctg atc gct cag gcc atc ctt cga gat tgcSer Ala Leu Ile Ala Gln Ala Ile Leu Arg Asp Cystgt tcc aat cct ccc tgt tcc caa aat aat cca gacCys Ser Asn Pro Pro Cys Ser Gln Asn Asn Pro Asptgt atg taaagacgct gcttgctcca ggaccctctg Cys Met aaccacgacg t

TABLE 73 DNA Sequence (SEQ ID NO: 281) and ProteinSequence (SEQ ID NO: 282) of Vr1.2tct tat ggc agg tat gcc tca ccc gtc gac aga gcgSer Tyr Gly Arg Tyr Ala Ser Pro Val Asp Arg Alatct gcc ctg atc gct cag gcc atc ctt cga gat tgcSer Ala Leu Ile Ala Gln Ala Ile Leu Arg Asp Cystgc tcc aat cct cct tgt gcc cat aat aat cca gacCys Ser Asn Pro Pro Cys Ala His Asn Asn Pro Asptgt cgt taaagacgct gcttgctcca ggaccctctg Cys Arg aaccacgacg t

TABLE 74 DNA Sequence (SEQ ID NO: 283) and ProteinSequence (SEQ ID NO: 284) of A1.4tct gat ggc agg aat gcc gca gcc aac gac aaa gcgSer Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Alatct ggc atg agc gcg ctg gcc gtc aat gaa tgc tgtSer Gly Met Ser Ala Leu Ala Val Asn Glu Cys Cysacc aac cct gtc tgt cac gcg gaa cat caa gaa cttThr Asn Pro Val Cys His Ala Glu His Gln Glu Leu tgt gct aga aga cgc tgaCys Ala Arg Arg Arg

TABLE 75 DNA Sequence (SEQ ID NO: 285) and ProteinSequence (SEQ ID NO: 286) of A1.5tct gat ggc agg aat gcc gca gcc aac gac aaa gcgSer Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Alatct gac gtg atc acg ctg gcc ctc aag gga tgc tgtSer Asp Val Ile Thr Leu Ala Leu Lys Gly Cys Cystcc aac cct gtc tgt cac ttg gag cat tca aac cttSer Asn Pro Val Cys His Leu Glu His Ser Asn Leu tgt ggt aga aga cgc tgaCys Gly Arg Arg Arg

TABLE 76 DNA Sequence (SEQ ID NO: 287) and ProteinSequence (SEQ ID NO: 288) of A1.6tct gat ggc agg aat gcc gca gcc aac gac aaa gcgSer Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Alatct ggc atg agc gcg ctg gcc gtc aat gaa tgc tgtSer Gly Met Ser Ala Leu Ala Val Asn Glu Cys Cysacc aac cct gtc tgt cac gtg gaa cat caa gaa cttThr Asn Pro Val Cys His Val Glu His Gln Glu Leu tgt gct aga aga cgc tgaCys Ala Arg Arg Arg

TABLE 77 DNA Sequence (SEQ ID NO: 289) and ProteinSequence (SEQ ID NO: 290) of Af1.1atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ttc act tca gat cgt gca ttt cgtThr Val Val Ser Phe Thr Ser Asp Arg Ala Phe Argggc agg aat gcc gca gcc aaa gcg tct ggc ctg gtcGly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leu Valggt ctg acc gac aag agg caa gaa tgc tgt tct tatGly Leu Thr Asp Lys Arg Gln Glu Cys Cys Ser Tyrcct gcc tgt aac cta gat cat cca gaa ctt tgt ggt Pro Ala Cys Asn Leu Asp His Pro Glu Leu Cys Glytgaagacgct gatgctccag gaccctctga accacgacgt

TABLE 78 DNA Sequence (SEQ ID NO: 291) and ProteinSequence (SEQ ID NO: 292) of Af1.2atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thract gtc gtt tcc tcc act tca ggt cgt cgt gca tttThr Val Val Ser Ser Thr Ser Gly Arg Arg Ala Phecgt ggc agg aat gcc gca gcc aaa gcg tct gga ctgArg Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leugtc ggt ctg act gac agg aga cca gaa tgc tgt agtVal Gly Leu Thr Asp Arg Arg Pro Glu Cys Cys Sergat cct cgc tgt aac tcg act cat cca gaa ctt tgtAsp Pro Arg Cys Asn Ser Thr His Pro Glu Leu Cysggt gga aga cgc tgatgctcca ggaccctctg aaccacgacg Gly Gly Arg Arg t

TABLE 79 DNA Sequence (SEQ ID NO: 293) andProtein Sequence (SEQ ID NO: 294) of Ar1.2tct gat ggc agg aat gcc gca gcc aac gcg ttt gacSer Asp Gly Arg Asn Ala Ala Ala Asn Ala Phe Aspctg atc gat ctg acc gcc agg cta aat tgc tgt atgLeu Ile Asp Leu Thr Ala Arg Leu Asn Cys Cys Metatt ccc ccc tgt tgg aag aaa tat gga gac aga tgtIle Pro Pro Cys Trp Lys Lys Tyr Gly Asp Arg Cysagt gaa gta cgc tgatgctcca ggaccctctg aaccacgacg Ser Glu Val Arg t

TABLE 80 DNA Sequence (SEQ ID NO: 295) andProtein Sequence (SEQ ID NO: 296) of Ar1.3tct gat ggc agg aat gcc gca cgc aaa gcg ttt ggcSer Asp Gly Arg Asn Ala Ala Arg Lys Ala Phe Glytgc tgc gac tta ata ccc tgt ttg gag aga tat ggtCys Cys Asp Leu Ile Pro Cys Leu Glu Arg Tyr Glyaac aga tgt aat gaa gtg cac tgatgctcca ggaccctctgAsn Arg Cys Asn Glu Val His  aaccacgcga cgt

TABLE 81 DNA Sequence (SEQ ID NO: 297) andProtein Sequence (SEQ ID NO: 298) of Ar1.4tct gat ggc agc aat gcc gca gcc aac gag ttt gacSer Asp Gly Ser Asn Ala Ala Ala Asn Glu Phe Aspctg atc gct ctg acc gcc agg cta ggt tgc tgt aacLeu Ile Ala Leu Thr Ala Arg Leu Gly Cys Cys Asngtt aca ccc tgt tgg gag aaa tat gga gac aaa tgtVal Thr Pro Cys Trp Glu Lys Tyr Gly Asp Lys Cysaat gaa gta cgc tgatgcttca ggaccctctg aaccacgacg Asn Glu Val Arg T

TABLE 82 DNA Sequence (SEQ ID NO: 299) andProtein Sequence (SEQ ID NO: 300) of Ar1.5tct gat ggc agg aat gtc gca gca aaa gcg ttt cacSer Asp Gly Arg Asn Val Ala Ala Lys Ala Phe Hiscgg atc ggc cgg acc atc agg gat gaa tgc tgt tccArg Ile Gly Arg Thr Ile Arg Asp Glu Cys Cys Seraat cct gcc tgt agg gtg aat aat cca cac gtt tgtAsn Pro Ala Cys Arg Val Asn Asn Pro His Val Cysaga cga cgc tgatgctcca ggaccctctg aaccacgacg t Arg Arg Arg

TABLE 83 DNA Sequence (SEQ ID NO: 301) andProtein Sequence (SEQ ID NO: 302) of Ar1.6tct gat ggc agg aat gcc gca gcc aac gcg ttt gacSer Asp Gly Arg Asn Ala Ala Ala Asn Ala Phe Aspctg atg cct ctg acc gcc agg cta aat tgc tgt agcLeu Met Pro Leu Thr Ala Arg Leu Asn Cys Cys Seratt ccc ggc tgt tgg aac gaa tat aaa gac aga tgtIle Pro Gly Cys Trp Asn Glu Tyr Lys Asp Arg Cysagt aaa gta cgc tgatgctcca ggaccctctg aaccacgacgt Ser Lys Val Arg

TABLE 84 DNA Sequence (SEQ ID NO: 303) andProtein Sequence (SEQ ID NO: 304) of Ay1.2tctgatggca ggaatgccgc agccgacgac aaagcgtctg                                           acctggtcgc t ctg gtc gtc agg gga gga tgc tgt tcc             Leu Val Val Arg Gly Gly Cys Cys Sercac cct gtc tgt tac ttt aat aat cca caa atg tgtHis Pro Val Cys Tyr Phe Asn Asn Pro Gln Met Cyscgt gga aga cgc tgatgctcca ggaccctctg aaccacgacg Arg Gly Arg Arg t

TABLE 85 DNA Sequence (SEQ ID NO: 305) andProtein Sequence (SEQ ID NO: 306) of Ay1.3tctgatggca ggaatgccgc agccgacgac aaagcgtctg                                           acctggtcgc t ctg gcc gtc agg gga gga tgc tgt tcc             Leu Ala Val Arg Gly Gly Cys Cys Sercac cct gtc tgt aac ttg aat aat cca caa atg tgtHis Pro Val Cys Asn Leu Asn Asn Pro Gln Met Cyscgt gga aga cgc tgatgctccaggaccctctg aaccacgacg t Arg Gly Arg Arg

TABLE 86 DNA Sequence (SEQ ID NO: 307) andProtein Sequence (SEQ ID NO: 308) of Bt1.8ttt cgt ggc agg aat ccc gca gcc aac gac aaa aggPhe Arg Gly Arg Asn Pro Ala Ala Asn Asp Lys Argtct gac ctg gcc get ctg agc gtc agg gga gga tgcSer Asp Leu Ala Ala Leu Ser Val Arg Gly Gly Cystgt tcc cat cct gcc tgt agc gtg act cat cca gagCys Ser His Pro Ala Cys Ser Val Thr His Pro Gluctt tgt ggc tgaagacgct gatgccccag gaccctctga Leu Cys Gly accacgacgt

TABLE 87 DNA Sequence (SEQ ID NO: 309) andProtein Sequence (SEQ ID NO: 310) of Bt1.9tct gat ggc ggg aat gcc gca gcc aaa gcg tct gacSer Asp Gly Gly Asn Ala Ala Ala Lys Ala Ser Aspctg atc gct cag acc atc agg gga gga tgc tgt tccLeu Ile Ala Gln Thr Ile Arg Gly Gly Cys Cys Sertat cct gcc tgt agc gtg gaa cat caa gac ctt tgtTyr Pro Ala Cys Ser Val Glu His Gln Asp Leu Cysgat gga aga cgc tgatgctcca ggaccctctg aaccacgacg Asp Gly Arg Arg t

TABLE 88 DNA Sequence (SEQ ID NO: 311) andProtein Sequence (SEQ ID NO: 312) of Ca1.3tct tat ggc agg aat gcc gca gcc aaa gcg ttt gaaSer Tyr Gly Arg Asn Ala Ala Ala Lys Ala Phe Glugtg agt tgc tgt gtc gtt cgc ccc tgt tgg att cgcVal Ser Cys Cys Val Val Arg Pro Cys Trp Ile Argtat caa gag gaa tgt ctt gaa gca gat ccc agg accTyr Gln Glu Glu Cys Leu Glu Ala Asp Pro Arg Thr ctc tga Leu

TABLE 89 DNA Sequence (SEQ ID NO: 313) andProtein Sequence (SEQ ID NO: 314) of Cal.4tct gat ggc agg aat gcc gca gcc aac gcc ctt gacSer Asp Gly Arg Asn Ala Ala Ala Asn Ala Leu Aspctg atc act ctg atc gcc agg caa aat tgc tgt agcLeu Ile Thr Leu Ile Ala Arg Gln Asn Cys Cys Seratt ccc ggc tgt tgg gag aaa tat gga gac aaa tgtIle Pro Gly Cys Trp Glu Lys Tyr Gly Asp Lys Cys agt gaa gta cgc tgaSer Glu Val Arg

TABLE 90 DNA Sequence (SEQ ID NO: 315) andProtein Sequence (SEQ ID NO: 316) of C1.2tct gat ggc agg aat gaa gca gcc aac gac gaa gcgSer Asp Gly Arg Asn Glu Ala Ala Asn Asp Glu Alatct gac gtg atc gag ctg gcc ctc aag gga tgc tgtSer Asp Val Ile Glu Leu Ala Leu Lys Gly Cys Cystcc aac cct gtc tgt cac ttg gag cat cca aac getSer Asn Pro Val Cys His Leu Glu His Pro Asn Alatgt ggt aga aga cgc tgatgctcca ggaccctctg Cys Gly Arg Arg Argaaccacgacg t

TABLE 91 DNA Sequence (SEQ ID NO: 317) andProtein Sequence (SEQ ID NO: 318) of C1.3tct gat ggc agg aat gcc gca gcc aac gac aaa gcgSer Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Alatct gac ctg gtc gct ctg gcc gtc agg gga tgc tgtSer Asp Leu Val Ala Leu Ala Val Arg Gly Cys Cystcc aac cct atc tgt tac ttt aat aat cca cga attSer Asn Pro Ile Cys Tyr Phe Asn Asn Pro Arg Iletgt cgt gga aga cgc tgatgctcca ggaccctctg Cys Arg Gly Arg Argaaccacgacg t

TABLE 92 DNA Sequence (SEQ ID NO: 319) andProtein Sequence (SEQ ID NO: 320) of Ep1.2tct cat ggc agg aat gcc gca cgc aaa gcg tct gacSer His Gly Arg Asn Ala Ala Arg Lys Ala Ser Aspctg atc gct ctg acc gtc agg gaa tgc tgt tct cagLeu Ile Ala Leu Thr Val Arg Glu Cys Cys Ser Glncct ccc tgt cgc tgg aaa cat cca gaa ctt tgt agtPro Pro Cys Arg Trp Lys His Pro Glu Leu Cys Ser tga

TABLE 93 DNA Sequence (SEQ ID NO: 321) andProtein Sequence (SEQ ID NO: 322) of G1.1tct gat ggc agg aat gac gca gcc aaa gcg ttt gacSer Asp Gly Arg Asn Asp Ala Ala Lys Ala Phe Aspctg ata tct tcg acc gtc aag aaa gga tgc tgt tccLeu Ile Ser Ser Thr Val Lys Lys Gly Cys Cys Sercat cct gcc tgt gcg ggg aat aat caa cat att tgtHis Pro Ala Cys Ala Gly Asn Asn Gln His Ile Cysggc cga aga cgc tgatgctcca ggaccctctg aaccacgacg Gly Arg Arg Arg t

TABLE 94 DNA Sequence (SEQ ID NO: 323) andProtein Sequence (SEQ ID NO: 324) of G1.3tct gat ggc agg aat gcc gca gcc aac gac caa gcgSer Asp Gly Arg Asn Ala Ala Ala Asn Asp Gln Alatct gac ctg atg gct gcg acc gtc agg gga tgc tgtSer Asp Leu Met Ala Ala Thr Val Arg Gly Cys Cysgcc gtt cct tcc tgt cgc ctc cgt aat cca gac cttAla Val Pro Ser Cys Arg Leu Arg Asn Pro Asp Leutgt ggt gga gga cgc tgatgctcca ggaccctctg Cys Gly Gly Gly Argaaccacgacg t

TABLE 95 DNA Sequence (SEQ ID NO: 325) andProtein Sequence (SEQ ID NO: 326) of Im1.3ctt gat gaa agg aat gcc gca gcc gac gac aaa gcgLeu Asp Glu Arg Asn Ala Ala Ala Asp Asp Lys Alatct gac ctg atc gct caa atc gtc agg aga gga tgcSer Asp Leu Ile Ala Gln Ile Val Arg Arg Gly Cystgt tcc cat cct gcc tgt aac gtg aat aat cca cacCys Ser His Pro Ala Cys Asn Val Asn Asn Pro His att tgt ggt tgaIle Cys Gly

TABLE 96 DNA Sequence (SEQ ID NO: 327) andProtein Sequence (SEQ ID NO: 328) of Lv1.2tct gat ggc agg aat act gca gcc aaa gtc aaa tatSer Asp Gly Arg Asn Thr Ala Ala Lys Val Lys Tyrtct aag acg ccg gag gaa tgc tgt ccc aat cct cccSer Lys Thr Pro Glu Glu Cys Cys Pro Asn Pro Protgt ttc gcg aca aat tcg gat att tgt ggc gga agaCys Phe Ala Thr Asn Ser Asp Ile Cys Gly Gly Argcgc tgatgctcca ggaccctctg aaccacgacg t Arg

TABLE 97 DNA Sequence (SEQ ID NO: 329) andProtein Sequence (SEQ ID NO: 330) of Lv1.3tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcgSer Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Alacct gcc ctg atg aag cgg acc gtc agg gat gct tgcPro Ala Leu Met Lys Arg Thr Val Arg Asp Ala Cystgt tca gac cct cgc tgt tcc ggg aaa cat caa gacCys Ser Asp Pro Arg Cys Ser Gly Lys His Gln Aspctg tgt ggc tgaagacgct gatgctccag gaccctctga Leu Cys Gly accacgacgt

TABLE 98 DNA Sequence (SEQ ID NO: 331) andProtein Sequence (SEQ ID NO: 332) of Lv1.4tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcgSer Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Alacct gcc ctg atg gag ctg acc gtc agg gaa gat tgcPro Ala Leu Met Glu Leu Thr Val Arg Glu Asp Cystgt tca gac cct cgc tgt tcc gtg gga cat caa gacCys Ser Asp Pro Arg Cys Ser Val Gly His Gln Aspctg tgt ggc tgaagacgct gatgctccag gaccctctga Leu Cys Gly Accacgacgt

TABLE 99 DNA Sequence (SEQ ID NO: 333) andProtein Sequence (SEQ ID NO: 334) of Lv1.6gca ttt gat ggc agg aat gct gca gcc agc gac aaaAla Phe Asp Gly Arg Asn Ala Ala Ala Ser Asp Lysgcg tcc gag ctg atg gct ctg gcc gtc agg gga tgc Ala Ser Glu Leu Met Ala Leu Ala Val Arg Gly Cystgt tcc cat cct gcc tgt gct ggg agt aat gca cat Cys Ser His Pro Ala Cys Ala Gly Ser Asn Ala Hisatc tgt ggc aga aga cgc tgatgctcca ggaccctctg Ile Cys Gly Arg Arg Argaaccacgacg t

TABLE 100 DNA Sequence (SEQ ID NO: 335) andProtein Sequence (SEQ ID NO: 336) of Lv1.7tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcgSer Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Alacct gcc ctg atg aag ctg acc gtc agg gag gat tgcPro Ala Leu Met Lys Leu Thr Val Arg Glu Asp Cystgt tca gac cct cgc tgt tcc gtg gga cat caa gacCys Ser Asp Pro Arg Cys Ser Val Gly His Gln Aspatg tgt ggc tgaagacgct gatgctccag gaccctctga Met Cys Gly atcacgacgt

TABLE 101 DNA Sequence (SEQ ID NO: 337) andProtein Sequence (SEQ ID NO: 338) of Lv1.8ttt gaa tgc agg aat gct gca ggc aac gac aaa gcgPhe Glu Cys Arg Asn Ala Ala Gly Asn Asp Lys Alaact gac ctg atg gct ctg act gtc agg gga tgc tgtThr Asp Leu Met Ala Leu Thr Val Arg Gly Cys Cystcc cat cct gcc tgt gct ggg aat aat cca cat atcSer His Pro Ala Cys Ala Gly Asn Asn Pro His Iletgc ggc tgaagacgct gatgctccag gaccctctga Cys Gly accacgacgt

TABLE 102 DNA Sequence (SEQ ID NO: 339) andProtein Sequence (SEQ ID NO: 340) of Lv1.9ttt gat ggc agg aac gcc gca gcc aac aac aaa gcgPhe Asp Gly Arg Asn Ala Ala Ala Asn Asn Lys Alaact gat ctg atg gct ctg act gtc aga gga tgc tgtThr Asp Leu Met Ala Leu Thr Val Arg Gly Cys Cysggc aat cct tca tgt agc atc cat att cct tac gttGly Asn Pro Ser Cys Ser Ile His Ile Pro Tyr Valtgt aat tagagacact gatgctccag gaccctctga Cys Asn accacgacgt

TABLE 103 DNA Sequence (SEQ ID NO: 341) andProtein Sequence (SEQ ID NO: 342) of Lv1.10tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcgSer Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Alacct gcc ctg atg aag cgg acc gac agc gaa gaa tgcPro Ala Leu Met Lys Arg Thr Asp Ser Glu Glu Cystgt tta gac tct cgc tgt gcc ggg caa cat caa gacCys Leu Asp Ser Arg Cys Ala Gly Gln His Gln Aspctg tgt ggc gga aga cgc tgatgctcca ggaccctctg Leu Cys Gly Gly Arg Argaaccacgacg t

TABLE 104 DNA Sequence (SEQ ID NO: 343) andProtein Sequence (SEQ ID NO: 344) of Mr1.3tct gat ggc agg aat gcc gca gcc aag gac aaa gcgSer Asp Gly Arg Asn Ala Ala Ala Lys Asp Lys Alatct gac ctg gtc gct ctg acc gtc aag gga tgc tgtSer Asp Leu Val Ala Leu Thr Val Lys Gly Cys Cystct aat cct ccc tgt tac gcg aat aat caa gcc tatSer Asn Pro Pro Cys Tyr Ala Asn Asn Gln Ala Tyr tgt aat gga aga cgc tgaCys Asn Gly Arg Arg

TABLE 105 DNA Sequence (SEQ ID NO: 345) andProtein Sequence (SEQ ID NO: 346) of Mr1.4tct gat ggc agg aat gcc gca gcc aag gac aaa gcgSer Asp Gly Arg Asn Ala Ala Ala Lys Asp Lys Alatct gac ctg gtc gct ctg acc gtc aag gga tgc tgtSer Asp Leu Val Ala Leu Thr Val Lys Gly Cys Cystct cat cct gcc tgt agc gtg aat aat cca gac attSer His Pro Ala Cys Ser Val Asn Asn Pro Asp Ile tgt ggt tga Cys Gly

TABLE 106 DNA Sequence (SEQ ID NO: 347) andProtein Sequence (SEQ ID NO: 348) of Ms1.1tct gat ggc agg aat gct gca gcc aac aac aaa gtgSer Asp Gly Arg Asn Ala Ala Ala Asn Asn Lys Valgct ttg acc atg agg gga aaa tgc tgt atc aat gatAla Leu Thr Met Arg Gly Lys Cys Cys Ile Asn Aspgcg tgt cgc tcg aaa cat cca cag tac tgt tct ggaAla Cys Arg Ser Lys His Pro Gln Tyr Cys Ser Glyaga cgc tgatactcca ggaccctctg aaccacgacg t Arg Arg

TABLE 107 DNA Sequence (SEQ ID NO: 349) andProtein Sequence (SEQ ID NO: 350) of Ms1.6tct gat ggc agg aat gct gca gcc aac gac aaa gtgSer Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Valtct gac cag atg gct ctg gtt gtc agg gga tgc tgtSer Asp Gln Met Ala Leu Val Val Arg Gly Cys Cystac aat att gcc tgt aga att aat aat cca cgg tacTyr Asn Ile Ala Cys Arg Ile Asn Asn Pro Arg Tyrtgt cgt gga aaa cgc tgatgttcca ggaccctctg Cys Arg Gly Lys Argaaccacgacg t

TABLE 108 DNA Sequence (SEQ ID NO: 351) andProtein Sequence (SEQ ID NO: 352) of O1.1tctgaaggca ggaatgccgc agccaacgac aaagcgtctgacctgatggc t ctg aac gtc agg gga tgc tgt tcc cat             Leu Asn Val Arg Gly Cys Cys Ser Hiscct gtc tgt cgc ttc aat tat cca aaa tat tgt ggtPro Val Cys Arg Phe Asn Tyr Pro Lys Tyr Cys Glygga aga cgc tgatggtcca ggaccctctg aaccacgacg t Gly Arg Arg

TABLE 109 DNA Sequence (SEQ ID NO: 353) andProtein Sequence (SEQ ID NO: 354) of O1.2tctgatggcg ggaatgccgc agcaaaagcg tttgatctaa tcactctg gcc ctc agg gat gaa tgc tgt gcc agt cct cccLeu Ala Leu Arg Asp Glu Cys Cys Ala Ser Pro Protgt cgt ttg aat aat cca tac gta tgt catCys Arg Leu Asn Asn Pro Tyr Val Cys Histgacgacgct gatgctccag gaccctctga accacgacgt

TABLE 110 DNA Sequence (SEQ ID NO: 355) andProtein Sequence (SEQ ID NO: 356) of O1.4atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ccc act tca gat cgt gca tct gatThr Val Val Ser Pro Thr Ser Asp Arg Ala Ser Aspagg agg aat gcc gca gcc aaa gcg ttt gac ctg agaArg Arg Asn Ala Ala Ala Lys Ala Phe Asp Leu Argtat tcg acc gcc aag aga gga tgc tgt tcc aat cctTyr Ser Thr Ala Lys Arg Gly Cys Cys Ser Asn Progtc tgt tgg cag aat aat gca gaa tac tgt cgt gaaVal Cys Trp Gln Asn Asn Ala Glu Tyr Cys Arg Gluagt ggc taatgctcca ggaccctctg aaccacgacg t Ser Gly

TABLE 111 DNA Sequence (SEQ ID NO: 357) andProtein Sequence (SEQ ID NO: 358) of O1.7atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ala Thracc gtc gtt tcc ttc act tca gat cgt gca tct gatThr Val Val Ser Phe Thr Ser Asp Arg Ala Ser Aspggc ggg aat gtc gca gcg tct cac ctg atc get ctgGly Gly Asn Val Ala Ala Ser His Leu Ile Ala Leuacc atc aag gga tgc tgt tct cac cct ccc tgt gccThr Ile Lys Gly Cys Cys Ser His Pro Pro Cys Alacag aat aat caa gac tat tgt ggt tgacgacgct Gln Asn Asn Gln Asp Tyr Cys Gly gatgctccag gaccctctga accacgacgt

TABLE 112 DNA Sequence (SEQ ID NO: 359) andProtein Sequence (SEQ ID NO: 360) of O1.8atg ttc acc gtg ttt ctg ttg gtt gtc tta tca accMet Phe Thr Val Phe Leu Leu Val Val Leu Ser Thracc gtc gtt tcc tcc act tca gat cgt gca tct gatThr Val Val Ser Ser Thr Ser Asp Arg Ala Ser Aspagg agg aat gcc gca gcc aaa gcg tct gac ctg atgArg Arg Asn Ala Ala Ala Lys Ala Ser Asp Leu Mettat tcg acc gtc aag aaa gga tgt tgt tcc cat cctTyr Ser Thr Val Lys Lys Gly Cys Cys Ser His Progcc tgt tcg ggg aat aat cga gaa tat tgt cgt gaaAla Cys Ser Gly Asn Asn Arg Glu Tyr Cys Arg Gluagt ggc taatgctcca ggaccctctg aaccacgacg t Ser Gly

TABLE 113 DNA Sequence (SEQ ID NO: 361) andProtein Sequence (SEQ ID NO: 362) of Om1.2tttgatggca ggaatgcctc agccgacagc aaagtggctgcccggatcgc t cag atc gac agg gat cca tgc tgt tcc             Gln Ile Asp Arg Asp Pro Cys Cys Sertat cct gac tgt ggc gcg aat cat cca gag att tgtTyr Pro Asp Cys Gly Ala Asn His Pro Glu Ile Cysggt gga aaa cgc tgatgctcca ggaccctctg aaccacgacg Gly Gly Lys Arg t

TABLE 114 DNA Sequence (SEQIDNO: 363) andProtein Sequence (SEQ ID NO: 364) of Om1.3tctcatggca ggaatgccgc acgct ctg acc gtc agg gaa                            Leu Thr Val Arg Glutgc tgt tct cag cct cct tgt cgc tgg aaa cat ccaCys Cys Ser Gln Pro Pro Cys Arg Trp Lys His Progaa ctt tgt agt tgaagacgct gatgctccag gaccctctga Glu Leu Cys Seraccacgacgt

TABLE 115 DNA Sequence (SEQ ID NO: 365) andProtein Sequence (SEQ ID NO: 366) of Om1.4tttgatggca ggaatgctgc agccagcgac aaagcgtctgagctgatggc t ctg gcc gtc agg gga tgc tgt tcc cat             Leu Ala Val Arg Gly Cys Cys Ser Hiscct gcc tgt get ggg aat aat cca cat atc tgt ggcPro Ala Cys Ala Gly Asn Asn Pro His Ile Cys Glyaga aga cgc tgatgctcca ggaccctctg aaccacgacg t Arg Arg Arg

TABLE 116 DNA Sequence (SEQ ID NO: 367) andProtein Sequence (SEQ ID NO: 368) of Om1.5tctggtgtca ggaaagacgc agcgcctggc ctgatcgct ctg                                           Leu acc atc aag gga tgc tgt tct gat cct agc tgt aacThr Ile Lys Gly Cys Cys Ser Asp Pro Ser Cys Asngtg aat aat cca gac tat tgt ggt tgacgacgct Val Asn Asn Pro Asp Tyr Cys Gly gatgctccag gaccctctga accacgacgt

TABLE 117 DNA Sequence (SEQ ID NO: 369) andProtein Sequence (SEQ ID NO: 370) of Om1.6tctaatggca ggaatgccgc agccaaattc aaagcgcctgccctgatgga g ctg acc gtc agg gaa gaa tgc tgt tcc             Leu Thr Val Arg Glu Glu Cys Cys Sergac cct cgc tgt tcc gtg gga cat caa gat atg tgtAsp Pro Arg Cys Ser Val Gly His Gln Asp Met Cys cgg tgaagcacgt gatgctccag gaccctctga accacgacgt Arg

TABLE 118 DNA Sequence (SEQ ID NO: 371) andProtein Sequence (SEQ ID NO: 372) of P1.4act gat ggc agg aat gct gca gcc ata gcg ctt gacThr Asp Gly Arg Asn Ala Ala Ala Ile Ala Leu Aspctg atc gct ccg gcc gtc agg gga gga tgc tgt tccLeu Ile Ala Pro Ala Val Arg Gly Gly Cys Cys Seraat cct gcc tgt tta gtg aat cat cta gaa atg tgtAsn Pro Ala Cys Leu Val Asn His Leu Glu Met Cysggt aaa aga cgc tgatgcccca ggaccctctg aaccacgacg Gly Lys Arg Arg t

TABLE 119 DNA Sequence (SEQ ID NO: 373) andProtein Sequence (SEQ ID NO: 374) of P1.5tct gat ggc agg gat gcc gca gcc aac gac aaa gcgSer Asp Gly Arg Asp Ala Ala Ala Asn Asp Lys Alatct gac ctg atc gct ctg acc gcc agg aga gat ccaSer Asp Leu Ile Ala Leu Thr Ala Arg Arg Asp Protgc tgt ttc aat cct gcc tgt aac gtg aat aat ccaCys Cys Phe Asn Pro Ala Cys Asn Val Asn Asn Procag att tgt ggt tgaagacgct gatgctccag gaccctctga Gln Ile Cys Glyaccacgacgt

TABLE 120 DNA Sequence (SEQ ID NO: 375) andProtein Sequence (SEQ ID NO: 376) of P1.6tct gat ggc agg gat gct gag aaa aca ggc ttt gacSer Asp Gly Arg Asp Ala Glu Lys Thr Gly Phe Aspacg acc att gtg ccg gaa gac tgc tgt tcg gat cctThr Thr Ile Val Pro Glu Asp Cys Cys Ser Asp Protcc tgt tgg agg ctg cat agt tta get tgt act ggaSer Cys Trp Arg Leu His Ser Leu Ala Cys Thr Glyatt gta aac cgc tgatgctcca ggaccctctg aaccacgacg Ile Val Asn Arg t

TABLE 121 DNA Sequence (SEQ ID NO: 377) andProtein Sequence (SEQ ID NO: 378) of P1.8act gat ggc agg agt gct gca gcc ata gcg ttt gccThr Asp Gly Arg Ser Ala Ala Ala Ile Ala Phe Alactg atc gct ccg acc gtc tgc tgt act aat cct gccLeu Ile Ala Pro Thr Val Cys Cys Thr Asn Pro Alatgt ctc gtg aat aat ata cgc ttt tgt ggt gga agaCys Leu Val Asn Asn Ile Arg Phe Cys Gly Gly Argcgc tgatgcccca ggaccctctg aaccacgacg t Arg

TABLE 122 DNA Sequence (SEQ ID NO: 379) andProtein Sequence (SEQ ID NO: 380) of Rg1.1tct gat gga aga aat gcc gca agc gac gcc aaa gcgSer Asp Gly Arg Asn Ala Ala Ser Asp Ala Lys Alattt ccc cgg atc get cca atc gtc agg gac gaa tgcPhe Pro Arg Ile Ala Pro Ile Val Arg Asp Glu Cystgt agc gat cct agg tgt cac ggg aat aat cgg gacCys Ser Asp Pro Arg Cys His Gly Asn Asn Arg Aspcac tgt gct tgaagacgct gctgctccag gaccctctga His Cys Ala accacgacgt

TABLE 123 DNA Sequence (SEQ ID NO: 381) andProtein Sequence (SEQ ID NO: 382) of Rg1.3tct gat ggc agg aat acc gcg gcc gac gaa aaa gcgSer Asp Gly Arg Asn Thr Ala Ala Asp Glu Lys Alatcc gac ctg atc tct caa act gtc aag aga gat tgcSer Asp Leu Ile Ser Gln Thr Val Lys Arg Asp Cystgt tcc cat cct ctc tgt aga tta ttt gtt cca ggaCys Ser His Pro Leu Cys Arg Leu Phe Val Pro Glyctt tgt att tgaagacgctgctgctccag gaccctctga Leu Cys Ile accacgact

TABLE 124 DNA Sequence (SEQ ID NO: 383) and Protein Sequence(SEQ ID NO: 384) of Rg1.4tct gat ggc agg aat gcc gca gcc gac aac aaa gcg tct gac cta atcSer Asp Gly Arg Asn Ala Ala Ala Asp Asn Lys Ala Ser Asp Leu Ileget caa atc gtc agg aga gga tgc tgt tcc cat cct gtc tgt aaa gtgAla Gln Ile Val Arg Arg Gly Cys Cys Ser His Pro Val Cys Lys Valagg tat cca gac ctg tgt cgt tgaagacgct gctgctccag gaccctctgaArg Tyr Pro Asp Leu Cys Arg accacgacgt

TABLE 125 DNA Sequence (SEQ ID NO: 385) and Protein Sequence(SEQ ID NO: 386) of Rg1.5tct gat ggc agg aat gcc gca gcc gac aac aga gcg tct gac cta atcSer Asp Gly Arg Asn Ala Ala Ala Asp Asn Arg Ala Ser Asp Leu Ilegct caa atc gtc agg aga gga tgc tgt tcc cat cct gcc tgt aat gtgAla Gln Ile Val Arg Arg Gly Cys Cys Ser His Pro Ala Cys Asn Valaat aat cca cac att tgt ggt tgaagacgct gctgctccag gaccctctgaAsn Asn Pro His Ile Cys Gly accacgacgt

TABLE 126 DNA Sequence (SEQ ID NO: 387) and Protein Sequence(SEQ ID NO: 388) of Rg1.8tct gat ggc agg aat gcc gca gcc gac aac aaa ccg tct gac cta atcSer Asp Gly Arg Asn Ala Ala Ala Asp Asn Lys Pro Ser Asp Leu Ilegct caa atc gtc agg aga gga tgc tgt tcg cat cct gtc tgt aaa gtgAla Gln Ile Val Arg Arg Gly Cys Cys Ser His Pro Val Cys Lys Valagg tat tca gac atg tgt ggt tgaagacgct gctgctccag gaccctctgaArg Tyr Ser Asp Met Cys Gly accacgacgt

TABLE 127 DNA Sequence (SEQ ID NO: 389) and Protein Sequence(SEQ ID NO: 390) of Sm1.4tct gat ggc agg aat gca gag cga cga caa agc gtc tgt cct ggt cgcSer Asp Gly Arg Asn Ala Glu Arg Arg Gln Ser Val Cys Pro Gly Argtct ggc ccc agg gga gga tgt tgt tcc cac cct gcc tgt aag gtg catSer Gly Pro Arg Gly Gly Cys Cys Ser His Pro Ala Cys Lys Val Histtt cca cac agt tgt ggt tgacgacgct gatgctccag gaccctctgaPhe Pro His Ser Cys Gly accacgacgt

TABLE 128 DNA Sequence (SEQ ID NO: 391) and Protein Sequence(SEQ ID NO: 392) of Sm1.5tct gat ggc agg aat gcc gca gcc agc gac aga gcg tct gac gcg gccSer Asp Gly Arg Asn Ala Ala Ala Ser Asp Arg Ala Ser Asp Ala Alacac cag gta tgc tgt tcc aac cct gtc tgt cac gtg gat cat cca gaaHis Gln Val Cys Cys Ser Asn Pro Val Cys His Val Asp His Pro Gluctt tgt cgt aga aga cgc tgatgctcca ggaccctctg aaccacgacg tLeu Cys Arg Arg Arg Arg

TABLE 129 DNA Sequence (SEQ ID NO: 393) and Protein Sequence(SEQ ID NO: 394) of S1.5tct gat ggc agg aat gcc gcg gcc aac gac aaa gcg tct gac ctg gtcSer Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Asp Leu Valgct ccg gcc atc agg gga tgc tgt tcc cac cct gtc tgt aac ttg agtAla Pro Ala Ile Arg Gly Cys Cys Ser His Pro Val Cys Asn Leu Seraat cca caa att tgt cgt gga aga cgc tgatgctcca ggaccctctgAsn Pro Gln Ile Cys Arg Gly Arg Arg aaccacgacg t

TABLE 130 DNA Sequence (SEQ ID NO: 395) and Protein Sequence(SEQ ID NO: 396) of Tx1.5ttt cat ggc agg aat gcc gca gcc aaa gcg tct ggc ctg gtc ggt ctgPhe His Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leu Val Gly Leuacc gac aag agg caa gaa tgc tgt tct cat cct gcc tgt aac gta gatThr Asp Lys Arg Gln Glu Cys Cys Ser His Pro Ala Cys Asn Val Aspcat cca gaa att tgt cgt tga His Pro Glu Ile Cys Arg

TABLE 131 DNA Sequence (SEQ ID NO: 397) and Protein Sequence(SEQ ID NO: 398) of T1.1act gat ggc agg agt gct gca gcc ata gcg ttt gcc ctg atc gct ccgThr Asp Gly Arg Ser Ala Ala Ala Ile Ala Phe Ala Leu Ile Ala Proacc gtc tgg gaa gga tgc tgt tct aat cct gcc tgt ctc gtg aat catThr Val Trp Glu Gly Cys Cys Ser Asn Pro Ala Cys Leu Val Asn Hisata cgc ttt tgt ggt gga aga cgc tgatgcccca ggaccctctg aaccacgacgIle Arg Phe Cys Gly Gly Arg Arg t

TABLE 132 DNA Sequence (SEQ ID NO: 399) and Protein Sequence(SEQ ID NO: 400) of Vr1.3tct aat ggc atg aat gcc gca gcc atc agg aaa gcg tct gcc ctg gtgSer Asn Gly Met Asn Ala Ala Ala Ile Arg Lys Ala Ser Ala Leu Valgct cag atc gcc cat cga gac tgc tgt gac gat cct gcc tgc acc gtgAla Gln Ile Ala His Arg Asp Cys Cys Asp Asp Pro Ala Cys Thr Valaat aat cca ggc ctt tgc act tgaagatgct gctgccccag gaccctctgaAsn Asn Pro Gly Leu Cys Thr accacgacgt

TABLE 133 DNA Sequence (SEQ ID NO: 401) and Protein Sequence(SEQ ID NO: 402) of G1.2tct gat ggc ggg aat gcc gca gca aaa gag tct gac gtg atc gct ctgSer Asp Gly Gly Asn Ala Ala Ala Lys Glu Ser Asp Val Ile Ala Leuacc gtc tgg aaa tgc tgt acc att cct tcc tgt tat gag aaa aaa aaaThr Val Trp Lys Cys Cys Thr Ile Pro Ser Cys Tyr Glu Lys Lys Lysatt aaa gca tgt gtc ttt tgacgacgct gatgctccag gaccctctgaIle Lys Ala Cys Val Phe accacgacgt

TABLE 134 DNA Sequence (SEQ ID NO: 403) and Protein Sequence(SEQ ID NO: 404) of Rg1.12tct gat ggc gca gtc gac gac aaa gcg ttg gat cga atc gct gaa atcSer Asp Gly Ala Val Asp Asp Lys Ala Leu Asp Arg Ile Ala Glu Ilegtc agg aga gga tgc tgt ggc aat cct gcc tgt agc ggc tcc tcg aaaVal Arg Arg Gly Cys Cys Gly Asn Pro Ala Cys Ser Gly Ser Ser Lysgat gca ccc tct tgt ggt tgaagacgct gctgctccag gaccctctgaAsp Ala Pro Ser Cys Gly accacgacgt

It will be appreciated that the methods and compositions of the instantinvention can be incorporated in the form of a variety of embodiments,only a few of which are disclosed herein. It will be apparent to theartisan that other embodiments exist and do not depart from the spiritof the invention. Thus, the described embodiments are illustrative andshould not be construed as restrictive.

BIBLIOGRAPHY

-   Barnay, G. et al. (2000). J. Med. Chem.-   Bitan, G. et al. (1997). J. Peptide Res. 49:421-426.-   Blount, K. et al. (1992). Toxicon 30:835-842.-   Bodansky et al. (1966). Chem. Ind. 38:1597-98.-   Cartier, G. E. et al. (1996). J. Biol. Chem. 271:7522-7528.-   Cruz, L. J. at al. (1976). Verliger 18:302-308.-   Cruz, L. J. et al. (1987). J. Biol. Chem. 260:9280-9288.-   Fainzilber, M. et al. (1994). Biochemistry 33:9523-9529.-   Gray, W. R. et al. (1981). J. Biol. Chem. 256:4734-4740.-   Haack, J. A. et al. (1990). J. Biol. Chem. 265:6025-6029.-   Horiki, K. et al. (1978). Chemistry Letters 165-68.-   Hubry, V. et al. (1994). Reactive Polymers 22:231-241.-   Jacobsen, R. et al. (1997). J. Biol. Chem. 272:22531-22537.-   Johnson, D. S. et al. (1995). Mol. Pharmacol. 48:194-199.-   Kapoor (1970). J. Pharm. Sci. 59:1-27.-   Kornreich, W. D. et al. (1986). U.S. Pat. No. 4,569,967.-   Luo, S. et al. (1998). J. Neurosci. 18:8571-8679.-   Marshall, I. G. and Harvey, A. L. (1990). Toxicon 28:231-234.-   Martinez, J. S. et al. (1995). Biochem. 34:14519-14526.-   McIntosh, J. M. et al. (1982). Arch. Biochem. Biophys. 218:329-334.-   Mena, E. E. et al. (1990). Neurosci. Lett. 118:241-244.-   Methoden der Organischen Chemie (Houben-Weyl): Synthese von    Peptiden, E. Wunsch (Ed.), Georg Thieme Verlag, Stuttgart, Ger.    (1974).-   Myers, R. A. et al. (1991). Biochemistry 30:9370-9377.-   Nishiuchi, Y. et al. (1993). Int. J. Pept. Protein Res. 42:533-538.-   Nowak, L. et al. (1984). Nature 307:462-465.-   Olivera, B. M. et al. (1984). U.S. Pat. No. 4,447,356.-   Olivera, B. M. et al. (1985). Science 230:1338-1343.-   Olivera, B. M. et al. (1996). U.S. Pat. No. 5,514,774.-   Rivier, J. R. et al. (1978). Biopolymers 17:1927-38.-   Rivier, J. R. et al. (1987). Biochem. 26:8508-8512.-   Sambrook, J. et al. (1989). Molecular Cloning: A Laboratory Manual,    2nd Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.-   Schroder & Lubke (1965). The Peptides 1:72-75, Academic Press, NY.-   Shon, K.-J. et al. (1994). Biochemistry 33:11420-11425.-   Stewart and Young, Solid-Phase Peptide Synthesis, Freeman & Co., San    Francisco, Calif. (1969).-   Vale et al. (1978). U.S. Pat. No. 4,105,603.-   Van de Steen, P. et al. (1998). Critical Rev. in Biochem. and Mol.    Biol. 33:151-208.-   Zafaralla, G. C. et al. (1988). Biochemistry 27:7102-7105.-   Zhou L. M., et al. (1996). J. Neurochem. 66:620-628.-   U.S. Pat. No. 3,972,859.-   U.S. Pat. No. 3,842,067.-   U.S. Pat. No. 3,862,925.-   U.S. Pat. No. 5,550,050.-   PCT Published Application WO 92/19195.-   PCT Published Application WO 94/25503.-   PCT Published Application WO 95/01203.-   PCT Published Application WO 95/05452.-   PCT Published Application WO 96/02286.-   PCT Published Application WO 96/02646.-   PCT Published Application WO 96/11698.-   PCT Published Application WO 96/40871.-   PCT Published Application WO 96/40959.-   PCT Published Application WO 97/12635.

1. A substantially pure α-conotoxin peptide selected from the groupconsisting of: (SEQ ID NO: 4)Asp-Xaa₁-Cys-Cys-Ser-Asp-Ser-Arg-Cys-Gly-Xaa₂- Asn-Cys-Leu;(SEQ ID NO: 5) Ala-Cys-Cys-Ser-Asp-Arg-Arg-Cys-Arg-Xaa₃-Arg-Cys;(SEQ ID NO: 6) Phe-Thr-Cys-Cys-Arg-Arg-Gly-Thr-Cys-Ser-Gln-His- Cys;(SEQ ID NO: 7) Asp-Xaa₄-Cys-Cys-Arg-Arg-His-Ala-Cys-Thr-Leu-Ile- Cys;(SEQ ID NO: 8) Asp-Xaa₄-Cys-Cys-Arg-Xaa₅-Xaa₅-Cys-Thr-Leu-Ile- Cys;(SEQ ID NO: 10) Gly-Gly-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ala-Xaa₃- Arg-Cys;(SEQ ID NO: 11) Ile-Ala-Xaa₃-Asp-Ile-Cys-Cys-Ser-Xaa₁-Xaa₅-Asp-Cys-Asn-His-Xaa₂-Cys-Val; and (SEQ ID NO: 12)Gly-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Xaa₂-His-Gln-Cys,

wherein Xaa₁ is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys,N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Trp (D or L), halo-Trpor neo-Trp; Xaa₄ is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ is Pro orhydroxy-Pro; and the C-terminus contains a carboxyl or amide group, orderivatives thereof.
 2. The substantially pure α-conotoxin peptide ofclaim 1, which is modified to contain an O-glycan, an S-glycan or anN-glycan.
 3. A substantially pure α-conotoxin peptide having the genericformula II:Xaa₁-Xaa₂-Xaa₃-Xaa₄-Cys-Cys-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Cys-Xaa₉-Xaa₁₀-Xaa₁₁-Xaa₁₂-Xaa₁₃-Xaa₁₄-Cys-Xaa₁₅-Xaa₁₆-Xaa₁₂(SEQ ID NO: 2), wherein Xaa₁ is des-Xaa₁, Asp, Glu or γ-carboxy-Glu(Gla); Xaa₂ is des-Xaa₂, Gln, Ala, Asp, Glu, Gla; Xaa₃ is des-Xaa₃, Gly,Ala, Asp, Glu, Gla, Pro or hydroxy-Pro; Xaa₄ is des-Xaa₄, Gly, Glu, Gla,Gln, Asp, Asn, Pro or hydroxy-Pro; Xaa₅ is Ser, Thr, Gly, Glu, Gla, Asn,Trp (D or L), neo-Trp, halo-Trp, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basicamino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid;Xaa₆ is Asp, Asn, His, halo-His, Thr, Ser, Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnaturalhydroxy containing amino acid; Xaa₂ is Pro or hydroxy-Pro; Xaa₈ is Ala,Ser, Thr, Asp, Val, Ile, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnaturalhydroxy containing amino acid; Xaa₉ is Gly, Ile, Leu, Val, Ala, Thr,Ser, Pro, hydroxy-Pro, Phe, Trp (D or L), neo-Trp, halo-Trp, Arg,ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys,N,N,N-trimethyl-Lys, any unnatural basic amino acid or any unnaturalaromatic amino acid; Xaa₁₀ is Ala, Asn, Phe, Pro, hydroxy-Pro, Glu, Gla,Gln, His, halo-His, Val, Ser, Thr, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₁₁ is Thr, Ser, His, halo-His, Leu, Ile, Val, Asn,Met, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid,Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa₁₂ is Asn,Pro, hydroxy-Pro, Gln, Ser, Thr, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys N,N,N-trimethyl-Lys, any unnatural basicamino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid;Xaa₁₃ is des-Xaa₁₃, Gly, Thr, Ser, Pro, hydroxy-Pro, Tyr, nor-Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr orany unnatural hydroxy containing amino acid; Xaa₁₄ is des-Xaa₁₄, Ile,Val, Asp, Leu, Phe, Arg, ornithine, homoarginine, Lys, N-methyl-Lys,N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid,Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr or any unnatural hydroxy containing amino acid; and Xaa₁₅ isdes-Xaa₁₅, Gly, Ala, Met, Ser, Thr, Trp (D or L), neo-Trp, halo-Trp, anyunnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₁₆ is des-Xaa₁₆, Trp (D or L), neo-Trp, halo-Trp,any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; Xaa₁₇ is des-Xaa₁₇, Arg, ornithine, homoarginine, Lys,N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnaturalbasic amino acid; and the C-terminus contains a free carboxyl group oran amide group.
 4. A substantially pure α-conotoxin peptide of genericformula II of claim 3 selected from the group consisting of:(SEQ ID NO: 13) Cys-Cys-Ser-Asp-Xaa₅-Ala-Cys-Xaa₂-Gln-Thr-Xaa₅-Gly-Cys-Arg; (SEQ ID NO: 14)Cys-Cys-Xaa₁-Asn-Xaa₅-Ala-Cys-Arg-His-Thr-Gln- Gly-Cys; (SEQ ID NO: 15)Gly-Cys-Cys-Xaa₃-His-Xaa₅-Ala-Cys-Gly-Arg-His- Xaa₄-Cys; (SEQ ID NO: 16)Ala-Xaa₅-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂- His-Arg-Cys;(SEQ ID NO: 17) Ala-Xaa5-Gly-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂-His-Arg-Cys; (SEQ ID NO: 18)Xaa₅-Xaa₅-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂- His-Arg-Cys;(SEQ ID NO: 19) Asp-Xaa₁-Asn-Cys-Cys-Xaa₃-Asn-Xaa₅-Ser-Cys-Xaa₅-Arg-Xaa₅-Arg-Cys-Thr; (SEQ ID NO: 20)Gly-Cys-Cys-Ser-Thr-Xaa₅-Xaa₅-Cys-Ala-Val-Leu- Xaa₄-Cys; (SEQ ID NO: 21)Gly-Cys-Cys-Gly-Asn-Xaa₅-Asp-Cys-Thr-Ser-His- Ser-Cys; (SEQ ID NO: 42)Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ala-His-Asn- Asn-Xaa₅-Asp-Cys-Arg;(SEQ ID NO: 154) Gly-Cys-Cys-Xaa₄-Asn-Xaa₅-Val-Cys-Xaa₂-Xaa₂-Xaa₄-Xaa₄-Cys-Xaa₃-Xaa₂; (SEQ ID NO: 155)Xaa₆-Xaa₁-Xaa₅-Gly-Cys-Cys-Arg-His-Xaa₅-Ala-Cys- Gly-Xaa₂-Asn-Arg-Cys;(SEQ ID NO: 156) Cys-Cys-Ala-Asp-Xaa₅-Asp-Cys-Arg-Phe-Arg-Xaa₅- Gly-Cys;(SEQ ID NO: 157) Gly-Cys-Cys-Xaa₄-Asn-Xaa₅-Ser-Cys-Xaa₃-Xaa₅-Xaa₂-Thr-Xaa₄-Cys-Ser-Xaa₃-Xaa₂; (SEQ ID NO: 158)Cys-Cys-Ser-Asn-Xaa₅-Thr-Cys-Xaa₂-Xaa₁-Thr-Xaa₄- Gly-Cys;(SEQ ID NO: 159) Cys-Cys-Ala-Asn-Xaa₅-Ile-Cys-Xaa₂-Asn-Thr-Xaa₅-Gly-Cys; (SEQ ID NO: 160)Cys-Cys-Asn-Asn-Xaa₅-Thr-Cys-Xaa₂-Xaa₁-Thr-Xaa₄- Gly-Cys;(SEQ ID NO: 161) Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Xaa₂-Xaa₁-Thr-Xaa₄-Gly-Cys; (SEQ ID NO: 162)Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Ser-Asn-Xaa₅-Xaa₂-Cys-Gly; (SEQ ID NO: 163)Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Ser-Ala-Met-Ser- Xaa₅-Ile-Cys;(SEQ ID NO: 164) Gly-Cys-Cys-Xaa₂-Asn-Xaa₅-Xaa₄-Cys-Gly-Ala-Ser-Xaa₂-Thr-Xaa₄-Cys; (SEQ ID NO: 165)Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Phe-Ala-Thr- Asn-Xaa₅-Asp-Cys;(SEQ ID NO: 166) Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn-Asn-Xaa₅-Leu-Cys-Ala; (SEQ ID NO: 167)Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn-Asn-Xaa₅-Phe-Cys-Ala; (SEQ ID NO: 168)Asp-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ser-Gln-Asn-Asn- Xaa₅-Asp-Cys-Met; and(SEQ ID NO: 169) Asp-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ala-His-Asn-Asn-Xaa₅-Asp-Cys-Arg,

wherein Xaa₁ is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys,N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Trp (D or L), halo-Trpor neo-Trp; Xaa₄ is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ is Pro orhydroxy-Pro; and the C-terminus contains a carboxyl or amide group, orderivatives thereof.
 5. The substantially pure α-conotoxin peptide ofclaim 3, which is modified to contain an O-glycan, an S-glycan or anN-glycan.
 6. The substantially pure α-conotoxin peptide of claim 4 whichis modified to contain an O-glycan, an S-glycan or an N-glycan.
 7. Asubstantially pure α-conotoxin peptide selected from the groupconsisting of: (SEQ ID NO: 22)Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Leu-Xaa₁-His- Ser-Asn-Met-Cys;(SEQ ID NO: 23) Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Arg-Gln-Asn-Asn-Ala-Xaa₁-Xaa₄-Cys-Arg; (SEQ ID NO: 24)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 25)Xaa₅-Xaa₁-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 26)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Asp; (SEQ ID NO: 27)Xaa₅-Arg-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 28)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Gly-Ile-Cys-Arg; (SEQ ID NO: 29)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Thr-Cys-Arg; (SEQ ID NO: 30)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Val-Cys-Arg; (SEQ ID NO: 31)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Ile-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 32)Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg-Arg-Arg-Arg; (SEQ ID NO: 33)Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Val-Asn- His-Xaa₅-Xaa₁-Leu-Cys;(SEQ ID NO: 34) Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Val-Asn-His-Xaa₅-Xaa₁-Leu-Cys; (SEQ ID NO: 35)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His- Xaa₅-Xaa₁-Ile-Cys;(SEQ ID NO: 36) Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Xaa₂-Thr-Gln-Xaa₁-Xaa₅-Cys-Arg-Xaa₁-Ser; (SEQ ID NO: 37)Xaa₅-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Xaa₅-Xaa₁-Phe-Cys-Arg-Gln; (SEQ ID NO: 38)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Xaa₅-Xaa₁-Phe-Cys-Arg-Gln; (SEQ ID NO: 39)Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Ala-Met-Asn-Asn- Xaa₅-Asp-Xaa₄-Cys;(SEQ ID NO: 40) Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Phe-Leu-Asn-Asn-Xaa₅-Asp-Xaa₄-Cys; (SEQ ID NO: 41)Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ile-Ala-Xaa₂-Asn-Xaa₅-His-Met-Cys-Gly; (SEQ ID NO: 43)Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn-Xaa₅-His-Val-Cys-Arg-Gln; (SEQ ID NO: 44)Gly-Cys-Cys-Ser-Arg-Xaa₅-Ala-Cys-Ile-Ala-Asn-Asn- Xaa₅-Asp-Leu-Cys;(SEQ ID NO: 45) Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Val-Xaa₁-His-Xaa₅-Xaa₁-Leu-Cys-Arg-Arg-Arg-Arg; (SEQ ID NO: 46)Gly-Gly-Cys-Cys-Ser-Phe-Xaa₅-Ala-Cys-Arg-Xaa₂-Xaa₅-Arg-Xaa₅-Xaa₁-Met-Cys-Gly; (SEQ ID NO: 47)Xaa₅-Xaa₁-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Ser-Ser-His-Xaa₅-Xaa₁-Leu-Cys-Gly; (SEQ ID NO: 48)Xaa₅-Gln-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Val-Gly-His-Xaa₅-Xaa₁-Leu-Cys-Gly; (SEQ ID NO: 49)Xaa₆-Val-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Val-Gly-His-Xaa₅-Xaa₁-Ile-Cys-Gly; (SEQ ID NO: 50)Gly-Cys-Cys-Ser-Arg-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn-Asn- Xaa₅-Asp-Leu-Cys;(SEQ ID NO: 51) Xaa₅-Gln-Cys-Cys-Ser-His-Leu-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 52)Gly-Cys-Cys-Ser-Xaa₄-Phe-Asp-Cys-Arg-Met-Met-Phe-Xaa₅-Xaa₁-Met-Cys-Gly-Xaa₃-Arg; (SEQ ID NO: 53)Gly-Gly-Cys-Cys-Ser-Phe-Ala-Ala-Cys-Arg-Xaa₂-Xaa₄-Arg-Xaa₅-Xaa₁-Met-Cys-Gly; (SEQ ID NO: 54)Gly-Gly-Cys-Cys-Phe-His-Xaa₅-Val-Cys-Xaa₄-Ile-Asn-Leu-Leu-Xaa₁-Met-Cys-Arg-Gln-Arg; (SEQ ID NO: 55)Ser-Ala-Thr-Cys-Cys-Asn-Xaa₄-Xaa₅-Xaa₅-Cys-Xaa₄-Xaa₁-Thr-Xaa₄-Xaa₅-Xaa₁-Ser-Cys-Leu; (SEQ ID NO: 56)Ala-Cys-Cys-Ala-Xaa₄-Xaa₅-Xaa₅-Cys-Phe-Xaa₁-Ala-Xaa₄-Xaa₅-Xaa₁-Arg-Cys-Leu; (SEQ ID NO: 57)Asn-Ala-Xaa₁-Cys-Cys-Xaa₄-Xaa₄-Xaa₅-Xaa₅-Cys-Xaa₄-Xaa₁-Ala-Xaa₄-Xaa₅-Xaa₁-Ile-Cys-Leu; (SEQ ID NO: 170)Xaa₁-Cys-Cys-Thr-Asn-Xaa₅-Val-Cys-His-Ala-Xaa₁-His-Gln-Xaa₁-Leu-Cys-Ala-Arg-Arg-Arg; (SEQ ID NO: 171)Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Leu-Xaa₁-His- Ser-Asn-Leu-Cys;(SEQ ID NO: 172) Xaa₁-Cys-Cys-Thr-Asn-Xaa₅-Val-Cys-His-Val-Xaa₁-His-Gln-Xaa₁-Leu-Cys-Ala-Arg-Arg-Arg; (SEQ ID NO: 173)Xaa₆-Xaa₁-Cys-Cys-Ser-Xaa₄-Xaa₅-Ala-Cys-Asn-Leu-Asp-His-Xaa₅-Xaa₁-Leu-Cys; (SEQ ID NO: 174)Xaa₅-Xaa₁-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Ser-Thr-His-Xaa₅-Xaa₁-Leu-Cys-Gly; (SEQ ID NO: 175)Leu-Asn-Cys-Cys-Met-Ile-Xaa₅-Xaa₅-Cys-Xaa₃-Xaa₂-Xaa₂-Xaa₄-Gly-Asp-Arg-Cys-Ser-Xaa₁-Val-Arg; (SEQ ID NO: 176)Ala-Phe-Gly-Cys-Cys-Asp-Leu-Ile-Xaa₅-Cys-Leu-Xaa₁-Arg-Xaa₄-Gly-Asn-Arg-Cys-Asn-Xaa₁-Val-His; (SEQ ID NO: 177)Leu-Gly-Cys-Cys-Asn-Val-Thr-Xaa₅-Cys-Xaa₃-Xaa₁-Xaa₂-Xaa₄-Gly-Asp-Xaa₂-Cys-Asn-Xaa₁-Val-Arg; (SEQ ID NO: 179)Leu-Asn-Cys-Cys-Ser-Ile-Xaa₅-Gly-Cys-Xaa₃-Asn-Xaa₁-Xaa₄-Xaa₂-Asp-Arg-Cys-Ser-Xaa₂-Val-Arg; (SEQ ID NO: 180)Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Xaa₄-Phe-Asn-Asn-Xaa₅-Gln-Met-Cys-Arg; (SEQ ID NO: 181)Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Asn-Leu-Asn-Asn-Xaa₅-Gln-Met-Cys-Arg; (SEQ ID NO: 182)Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Xaa₄-Ala-Asn-Asn-Gln-Ala-Xaa₄-Cys-Asn; (SEQ ID NO: 183)Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Val-Thr- His-Xaa₅-Xaa₁-Leu-Cys;(SEQ ID NO: 184) Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Ala-Cys-Ser-Val-Xaa₁-His-Gln-Asp-Leu-Cys-Asp; (SEQ ID NO: 185)Val-Ser-Cys-Cys-Val-Val-Arg-Xaa₅-Cys-Xaa₃-Ile-Arg-Xaa₄-Gln-Xaa₁-Xaa₁-Cys-Leu-Xaa₁-Ala-Asp-Xaa₅-Arg- Thr-Leu;(SEQ ID NO: 186) Xaa₆-Asn-Cys-Cys-Ser-Ile-Xaa₅-Gly-Cys-Xaa₃-Xaa₁-Xaa₂-Xaa₄-Gly-Asp-Xaa₂-Cys-Ser-Xaa₁-Val-Arg; (SEQ ID NO: 187)Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Leu-Xaa₁- His-Xaa₅-Asn-Ala-Cys;(SEQ ID NO: 188) Gly-Cys-Cys-Ser-Asn-Xaa₅-Ile-Cys-Xaa₄-Phe-Asn-Asn-Xaa₅-Arg-Ile-Cys-Arg; (SEQ ID NO: 189)Xaa₁-Cys-Cys-Ser-Gln-Xaa₅-Xaa₅-Cys-Arg-Xaa₃-Xaa₂-His-Xaa₅-Xaa₁-Leu-Cys-Ser; (SEQ ID NO: 190)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn- Gln-His-Ile-Cys;(SEQ ID NO: 191) Gly-Cys-Cys-Ala-Val-Xaa₅-Ser-Cys-Arg-Leu-Arg-Asn-Xaa₅-Asp-Leu-Cys-Gly-Gly; (SEQ ID NO: 192)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asn-Asn- Xaa₅-His-Ile-Cys;(SEQ ID NO: 193) Thr-Xaa₅-Xaa₁-Xaa₁-Cys-Cys-Xaa₅-Asn-Xaa₅-Xaa₅-Cys-Phe-Ala-Thr-Asn-Ser-Asp-Ile-Cys-Gly; (SEQ ID NO: 194)Asp-Ala-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Gly-Xaa₂- His-Gln-Asp-Leu-Cys;(SEQ ID NO: 195) Xaa₁-Asp-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Leu-Cys; (SEQ ID NO: 196)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Ser-Asn- Ala-His-Ile-Cys;(SEQ ID NO: 197); Xaa₁-Asp-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys; (SEQ ID NO: 198)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn- Xaa₅-His-Ile-Cys;(SEQ ID NO: 199) Gly-Cys-Cys-Gly-Asn-Xaa₅-Ser-Cys-Ser-Ile-His-Ile-Xaa₅-Xaa₄-Val-Cys-Asn; (SEQ ID NO: 200)Thr-Asp-Ser-Xaa₁-Xaa₁-Cys-Cys-Leu-Asp-Ser-Arg-Cys-Ala-Gly-Gln-His-Gln-Asp-Leu-Cys-Gly; (SEQ ID NO: 201)Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Xaa₄-Ala-Asn-Asn-Gln-Ala-Xaa₄-Cys-Asn; (SEQ ID NO: 202)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Val-Asn-Asn- Xaa₅-Asp-Ile-Cys;(SEQ ID NO: 203) Gly-Xaa₂-Cys-Cys-Ile-Asn-Asp-Ala-Cys-Arg-Ser-Xaa₂-His-Xaa₅-Gln-Xaa₄-Cys-Ser; (SEQ ID NO: 204)Gly-Cys-Cys-Xaa₄-Asn-Ile-Ala-Cys-Arg-Ile-Asn-Asn- Xaa₅-Arg-Xaa₄-Cys-Arg;(SEQ ID NO: 205) Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Arg-Phe-Asn-Xaa₄-Xaa₅-Xaa₂-Xaa₄-Cys-Gly; (SEQ ID NO: 206)Asp-Xaa₁-Cys-Cys-Ala-Ser-Xaa₅-Xaa₅-Cys-Arg-Leu-Asn-Asn-Xaa₅-Xaa₄-Val-Cys-His; (SEQ ID NO: 207)Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Xaa₃-Gln-Asn-Asn-Ala-Xaa₁-Xaa₄-Cys-Arg-Xaa₁-Ser; (SEQ ID NO: 208)Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Ala-Gln-Asn-Asn- Gln-Asp-Xaa₄-Cys;(SEQ ID NO: 209) Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Arg-Xaa₁-Xaa₄-Cys-Arg-Xaa₁-Ser;  (SEQ ID NO: 210)Asp-Xaa₅-Cys-Cys-Ser-Xaa₄-Xaa₅-Asp-Cys-Gly-Ala-Asn-His-Xaa₅-Xaa₁-Ile-Cys-Gly; (SEQ ID NO: 211)Xaa₁-Cys-Cys-Ser-Gln-Xaa₅-Xaa₅-Cys-Arg-Xaa₃-Xaa₂-His-Xaa₅-Xaa₁-Leu-Cys-Ser; (SEQ ID NO: 212)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn- Xaa₅-His-Ile-Cys;(SEQ ID NO: 213) Gly-Cys-Cys-Ser-Asp-Xaa₅-Ser-Cys-Asn-Val-Asn-Asn-Xaa₅-Asp-Xaa₄-Cys; (SEQ ID NO: 214)Xaa₁-Xaa₁-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys-Arg; (SEQ ID NO: 215)Gly-Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Leu-Val-Asn- His-Leu-Xaa₁-Met-Cys;(SEQ ID NO: 216) Arg-Asp-Xaa₅-Cys-Cys-Phe-Asn-Xaa₅-Ala-Cys-Asn-Val-Asn-Asn-Xaa₅-Gln-Ile-Cys; (SEQ ID NO: 217)Cys-Cys-Ser-Asp-Xaa₅-Ser-Cys-Xaa₃-Arg-Leu-His-Ser-Leu-Ala-Cys-Thr-Gly-Ile-Val-Asn-Arg; (SEQ ID NO: 218)Cys-Cys-Thr-Asn-Xaa₅-Ala-Cys-Leu-Val-Asn-Asn-Ile- Arg-Phe-Cys-Gly;(SEQ ID NO: 219) Asp-Xaa₁-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-His-Gly-Asn-Asn-Arg-Asp-His-Cys-Ala; (SEQ ID NO: 220)Asp-Cys-Cys-Ser-His-Xaa₅-Leu-Cys-Arg-Leu-Phe-Val- Xaa₅-Gly-Leu-Cys-Ile;(SEQ ID NO: 221) Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Xaa₂-Val-Arg-Xaa₄-Xaa₅-Asp-Leu-Cys-Arg; (SEQ ID NO: 222)Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asn-Asn- Xaa₅-His-Ile-Cys;(SEQ ID NO: 223) Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Xaa₂-Val-Arg-Xaa₄-Ser-Asp-Met-Cys; (SEQ ID NO: 224)Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Xaa₂-Val-His- Phe-Xaa₅-His-Ser-Cys;(SEQ ID NO: 225) Val-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Val-Asp-His-Xaa₅-Xaa₁-Leu-Cys-Arg-Arg-Arg-Arg; (SEQ ID NO: 226)Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Asn-Leu-Ser-Asn- Xaa₅-Gln-Ile-Cys-Arg;(SEQ ID NO: 227) Xaa₆-Xaa₁-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa₁-Ile-Cys-Arg; (SEQ ID NO: 228)Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Leu-Val-Asn-His- Ile-Arg-Phe-Cys-Gly;(SEQ ID NO: 229) Asp-Cys-Cys-Asp-Asp-Xaa₅-Ala-Cys-Thr-Val-Asn-Asn-Xaa₅-Gly-Leu-Cys-Thr; and (SEQ ID NO: 230)Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ile-Ala-Xaa₂-Asn-Xaa₅-His-Met-Cys-Gly-Gly-Arg-Arg,

wherein Xaa₁ is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys,N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Trp (D or L), halo-Trpor neo-Trp; Xaa₄ is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ is Pro orhydroxy-Pro; Xaa₆ is Gln or pyro-Glu; and the C-terminus contains acarboxyl or amide group, or derivatives thereof.
 8. The substantiallypure α-conotoxin peptide of claim 7, which is modified to contain anβ-glycan, an S-glycan or an N-glycan.
 9. A substantially pureα-conotoxin peptide selected from the group consisting of:(SEQ ID NO: 231) Cys-Cys-Thr-Ile-Xaa₅-Ser-Cys-Xaa₄-Xaa₁-Xaa₂-Xaa₂-Xaa₂-Ile-Xaa₂-Ala-Cys-Val-Phe and (SEQ ID NO: 232)Gly-Cys-Cys-Gly-Asn-Xaa₅-Ala-Cys-Ser-Gly-Ser-Ser-Xaa₂-Asp-Ala-Xaa₅-Ser-Cys,

wherein Xaa₁ is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys,N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₄ is Tyr, nor-Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr;and Xaa₅ is Pro or hydroxy-Pro; and the C-terminus contains a carboxylor amide group, or derivatives thereof.
 10. The substantially pureα-conotoxin peptide of claim 9, which is modified to contain anO-glycan, an S-glycan or an N-glycan.